U.S. patent number 9,315,488 [Application Number 14/726,337] was granted by the patent office on 2016-04-19 for bcl-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases.
This patent grant is currently assigned to ABBVIE INC.. The grantee listed for this patent is AbbVie Inc.. Invention is credited to Hong Ding, Steven W. Elmore, Lisa Hasvold, Laura A. Hexamer, Aaron R. Kunzer, William J. McClellan, Andrew J. Souers, Gerard M. Sullivan, Zhi-Fu Tao, Michael D. Wendt.
United States Patent |
9,315,488 |
Ding , et al. |
April 19, 2016 |
Bcl-2-selective apoptosis-inducing agents for the treatment of
cancer and immune diseases
Abstract
Disclosed are compounds which inhibit the activity of
anti-apoptotic Bcl-2 or Bcl-xL proteins, compositions containing
the compounds and methods of treating diseases during which are
expressed anti-apoptotic Bcl-2 protein.
Inventors: |
Ding; Hong (Gurnee, IL),
Elmore; Steven W. (Northbrook, IL), Hasvold; Lisa
(Grayslake, IL), Hexamer; Laura A. (Grayslake, IL),
Kunzer; Aaron R. (Arlington Heights, IL), McClellan; William
J. (Waukegan, IL), Souers; Andrew J. (Evanston, IL),
Sullivan; Gerard M. (Lake Villa, IL), Tao; Zhi-Fu
(Gurnee, IL), Wendt; Michael D. (Vernon Hills, IL) |
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc. |
North Chicago |
IL |
US |
|
|
Assignee: |
ABBVIE INC. (North Chicago,
IL)
|
Family
ID: |
42481688 |
Appl.
No.: |
14/726,337 |
Filed: |
May 29, 2015 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20160009687 A1 |
Jan 14, 2016 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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14058164 |
Jul 7, 2015 |
9072748 |
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12631404 |
Oct 22, 2013 |
8563735 |
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61120275 |
Dec 5, 2008 |
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61181180 |
May 26, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D
471/04 (20130101); A61K 31/407 (20130101); A61P
25/32 (20180101); A61P 37/08 (20180101); C07D
211/96 (20130101); A61P 15/00 (20180101); A61P
29/00 (20180101); A61P 25/00 (20180101); A61P
43/00 (20180101); C07D 209/32 (20130101); A61K
31/496 (20130101); A61P 27/02 (20180101); A61P
35/02 (20180101); C07D 235/26 (20130101); C07D
405/14 (20130101); A61P 25/06 (20180101); C07D
417/12 (20130101); C07D 487/04 (20130101); C07D
231/56 (20130101); C07D 405/06 (20130101); A61P
11/06 (20180101); C07D 295/155 (20130101); A61P
1/18 (20180101); A61P 19/00 (20180101); A61P
19/02 (20180101); A61P 37/00 (20180101); C07D
403/06 (20130101); A61K 31/495 (20130101); A61P
35/00 (20180101); C07D 215/20 (20130101); A61P
11/00 (20180101); A61P 7/02 (20180101); A61P
17/00 (20180101); A61P 35/04 (20180101); C07D
209/08 (20130101); A61P 9/06 (20180101); A61P
9/10 (20180101); C07D 211/58 (20130101); C07D
213/64 (20130101); C07D 309/14 (20130101); A61P
3/10 (20180101); A61P 7/06 (20180101); A61P
31/04 (20180101); C07D 401/06 (20130101); A61P
19/10 (20180101); C07D 295/14 (20130101); A61K
31/5377 (20130101); A61P 7/00 (20180101); A61P
9/12 (20180101); C07D 249/04 (20130101); A61P
1/16 (20180101); A61P 31/00 (20180101); A61P
17/04 (20180101); A61P 21/00 (20180101); A61P
21/04 (20180101); A61P 31/10 (20180101); A61P
31/16 (20180101); A61P 25/16 (20180101); C07D
217/16 (20130101); A61P 5/14 (20180101); A61P
13/12 (20180101); C07D 413/06 (20130101); A61K
45/06 (20130101); C07D 309/04 (20130101); C07D
401/12 (20130101); A61P 37/06 (20180101); A61P
17/14 (20180101); A61P 21/02 (20180101); A61P
33/00 (20180101); A61P 25/28 (20180101); A61P
31/12 (20180101); C07D 241/04 (20130101); A61K
31/501 (20130101); A61P 9/00 (20180101); A61P
25/14 (20180101); C07D 295/125 (20130101); C07D
405/12 (20130101) |
Current International
Class: |
C07D
295/155 (20060101); C07D 401/12 (20060101); C07D
211/58 (20060101); C07D 209/08 (20060101); C07D
309/04 (20060101) |
References Cited
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WO |
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WO |
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Primary Examiner: Jackson; Shawquia
Attorney, Agent or Firm: Jones Day
Parent Case Text
This application is a continuation of U.S. patent application Ser.
No. 14/058,164, filed Oct. 18, 2013, which is a continuation of
U.S. patent application Ser. No. 12/631,404, filed Dec. 4, 2009,
which claims the benefit of U.S. Provisional Patent Application No.
61/120,275, filed Dec. 5, 2008, and U.S. Provisional Patent
Application No. 61/181,180, filed May 26, 2009, each of which is
hereby incorporated by reference in its entirety into this
application.
Claims
What is claimed is:
1. A compound, or a therapeutically acceptable salt thereof,
wherein the compound is selected from the group consisting of:
2-(benzyloxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)--
N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benza-
mide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nit-
ro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(2-phenylet-
hoxy)benzamide;
2-benzyl-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-
-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;
2-benzyl-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-
-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;
2-benzyl-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-
-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(2-phenylethyl)b-
enzamide;
2-(benzylamino)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sul-
fonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-methoxy-N-((-
3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide-
;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(di-
methylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-6-yloxy)benz-
amide;
N-[(3-{[chloro(difluoro)methyl]sulfonyl}-4-{[3-(dimethylamino)propy-
l]amino}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1--
en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenoxymethyl)b-
enzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-
-((3-morpholin-4-ylpropyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;
5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-1,1'-biphenyl-2-ca-
rboxamide;
5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((-
4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-1,1'-biphenyl-2-
-carboxamide;
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl-
)-2-phenoxybenzamide;
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-
-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benza-
mide;
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-in-
dol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-
benzamide;
4-{4-[1-(4'-chloro-1,14'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2--
(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sul-
fonyl)benzamide;
4-{4-[(1R)-1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-in-
dol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)benzamide;
4-{4-[(1S)-1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-in-
dol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)benzamide; and
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(py-
ridin-3-ylamino)benzamide.
2. A pharmaceutical composition comprising an excipient and a
therapeutically effective amount of the compound or therapeutically
acceptable salt of claim 1.
Description
FIELD OF THE INVENTION
This invention pertains to compounds which selectively inhibit the
activity of anti-apoptotic Bcl-2 family proteins, compositions
containing the compounds, and methods of treating diseases during
which anti-apoptotic Bcl-2 proteins are expressed.
BACKGROUND OF THE INVENTION
Anti-apoptotic Bcl-2 family proteins are associated with a number
of diseases and are under investigation as potential therapeutic
drug targets. These targets for interventional therapy include, for
example, the Bcl-2 family proteins Bcl-2, Bcl-X.sub.L and Bcl-w.
Recently, inhibitors of Bcl-2 family proteins have been reported in
commonly-owned PCT/US/2004/36770, published as WO 2005/049593 and
PCT/US/2004/367911, published as WO 2005/049594. While this art
teaches inhibitors having high binding to the target protein,
compound binding affinity is only one of many parameters to be
considered. One goal is to produce compounds that preferentially
bind to, that is, are selective for, one protein over another
protein. To exhibit this selectivity, it is well known that a
compound not only displays a high binding affinity to a particular
protein but a lower binding affinity for another member as
well.
A typical measure of binding affinity of an anti-apoptotic protein
inhibitor is the balance between the binding and dissociation
processes between the protein and the inhibitor (K.sub.i). The
inhibition constant (K.sub.i) is the dissociation constant of an
enzyme-inhibitor complex or a protein/small molecule complex,
wherein the small molecule is inhibiting binding of one protein to
another protein. So a large K.sub.i value indicates a low binding
affinity, and a small K.sub.i value indicates a high binding
affinity.
A typical measure of cellular activity of an anti-apoptotic protein
inhibitor is the concentration eliciting 50% cellular effect
(EC.sub.50).
Accordingly, the inventors have discovered that while compounds
taught in the art have utility for the treatment of various cancers
and immune diseases, they are not selective for anti-apoptotic
Bcl-2 proteins over anti-apoptotic Bcl-X.sub.L proteins and thereby
result in a higher probability of side effects characterized by
inhibition of anti-apoptotic Bcl-X.sub.L proteins such as,
thrombocytopenia.
This invention therefore comprises a series of compounds that
demonstrate unexpected properties with respect to their selectivity
for binding to, and inhibiting the activity of anti-apoptotic Bcl-2
protein over anti-apoptotic Bcl-X.sub.L protein as significantly
higher than those of the compounds taught in PCT/US/2004/36770 and
PCT/US/2004/367911.
SUMMARY OF THE INVENTION
One embodiment of this invention, therefore, pertains to compounds
or therapeutically acceptable salts, prodrugs or salts of prodrugs
thereof, which are useful as selective inhibitors one or more than
one anti-apoptotic protein family member, the compounds having
Formula (I)
##STR00001##
wherein A.sup.1 is N or C(A.sup.2);
one or two or three or each of A.sup.2, B.sup.1, D.sup.1 and
E.sup.1 are independently selected R.sup.1, OR.sup.1, SR.sup.1,
S(O)R.sup.1, SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1,
OC(O)R.sup.1, NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1,
C(O)N(R.sup.1).sub.2, NHC(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)NHR.sup.1, NR.sup.1C(O)N(R.sup.1).sub.2,
SO.sub.2NHR.sup.1, SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NHSO.sub.2NHR.sup.1 or N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, and
the remainder are independently selected H, F, Cl, Br, I, CN,
CF.sub.3, C(O)OH, C(O)NH.sub.2 or C(O)OR.sup.1A; and
Y.sup.1 is H, CN, NO.sub.2, C(O)OH, F, Cl, Br, 1, CF.sub.3,
OCF.sub.3, CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, R.sup.17,
OR.sup.17, C(O)R.sup.17, C(O)OR.sup.17, SR.sup.17, NH.sub.2,
NHR.sup.17, N(R.sup.17).sub.2, NHC(O)R.sup.17, C(O)NH.sub.2,
C(O)NHR.sup.17, C(O)N(R.sup.17).sub.2, NHS(O)R.sup.17 or
NHSO.sub.2R.sup.17;
or
B.sup.1 and Y.sup.1, together with the atoms to which they are
attached, are imidazole or triazole; and
one or two or each of A.sup.2, D.sup.1 and E.sup.1 are
independently selected R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NHC(O)OR.sup.1, NHC(O)NHR.sup.1,
N(CH.sub.3)C(O)N(CH.sub.3)R.sup.1, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1, NHSO.sub.7NHR.sup.1 or
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, and the remainder are
independently selected H, F, Cl, Br, I, CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
R.sup.1 is R.sup.2, R.sup.3, R.sup.4 or R.sup.5;
R.sup.1A is C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl or
C.sub.3-C.sub.6-alkynyl;
R.sup.2 is phenyl which is unfused or fused with arene, heteroarene
or R.sup.2A; R.sup.2A is cycloalkane or heterocycloalkane;
R.sup.3 is heteroaryl which is unfused or fused with benzene,
heteroarene or R.sup.3A; R.sup.3A is cycloalkane or
heterocycloalkane;
R.sup.4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with arene,
heteroarene or R.sup.4A; R.sup.4A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.5 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.6, NC(R.sup.6A)(R.sup.6B), R.sup.7, OR.sup.7,
SR.sup.7, S(O)R.sup.1, SO.sub.2R.sup.7, NHR.sup.7,
N(R.sup.7).sub.2, C(O)R.sup.7, C(O)NH.sub.2, C(O)NHR.sup.7,
NHC(O)R.sup.7, NHSO.sub.2R.sup.7, NHC(O)OR.sup.7, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2, NHC(O)NH.sub.2,
NHC(O)NHR.sup.7, NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NH.sub.2,
NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NHR.sup.1, OH, (O), C(O)OH,
(O), N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br
or I substituents;
R.sup.6 is C.sub.2-C.sub.5-spiroalkyl, each of which is
unsubstituted or substituted with OH, (O), N.sub.3, CN, CF.sub.3,
CF.sub.2CF.sub.3, F, Cl, Br, I, NH.sub.2, NH(CH.sub.3) or
N(CH.sub.3).sub.2;
R.sup.6A and R.sup.6B are independently selected alkyl or, together
with the N to which they are attached, R.sup.6C;
R.sup.6C is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl or
piperidin-1-yl, each having one CH.sub.2 moiety unreplaced or
replaced with O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or
NH;
R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
R.sup.8 is phenyl which is unfused or fused with arene, heteroarene
or R.sup.8A;
R.sup.8A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.9 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.9A; R.sup.9A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.10 is C.sub.3-C.sub.10-cycloalkyl or
C.sub.4-C.sub.10-cycloalkenyl, each having one or two CH/moieties
unreplaced or replaced with independently selected O, C(O), CNOH,
CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH moieties
unreplaced or replaced with N, and each of which is unfused or
fused with arene, heteroarene or R.sup.10A; R.sup.10A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.11 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.12, OR.sup.12, NHR.sup.12, N(R.sup.12).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.12, C(O)N(R.sup.12).sub.2, OH, (O),
C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl,
Br or I substituents;
R.sup.12 is R.sup.13, R.sup.14, R.sup.15, or R.sup.16;
R.sup.13 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.13A; R.sup.13A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.14 is heteroaryl, each of which is unfused or fused with
arene, heteroarene or R.sup.14A; R.sup.14A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.15 is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene, each of which is unfused or fused with arene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.16 is alkyl, alkenyl or alkynyl;
R.sup.17 is R.sup.18, R.sup.19, R.sup.20 or R.sup.21;
R.sup.18 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.18A; R.sup.18A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.19 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.19A; R.sup.19A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.20 is C.sub.3-C.sub.10-cycloalkyl or
C.sub.4-C.sub.10-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.20A; R.sup.20A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.21 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.22, OR.sup.22, NHR.sup.22, N(R.sup.22).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.22, C(O)N(R.sup.22).sub.2, OH, (O),
C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl,
Br or I substituents;
R.sup.22 is R.sup.23, R.sup.24 or R.sup.25;
R.sup.23 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.23A; R.sup.23A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.24 is heteroarene which is unfused or fused with arene,
heteroarene or R.sup.24A; R.sup.24A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.25 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.25A; R.sup.25A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
Z.sup.1 is R.sup.26 or R.sup.27, each of which is substituted with
R.sup.28, R.sup.29 or R.sup.30, each of which is substituted with
F, Cl, Br, I, CH.sub.2R.sup.37, CH(R.sup.31)(R.sup.37),
C(R.sup.31)(R.sup.31A)(R.sup.37), C(O)R.sup.37, OR.sup.37,
SR.sup.37, S(O)R.sup.37, SO.sub.2R.sup.37, NHR.sup.37 or
N(R.sup.32)R.sup.37;
R.sup.26 is phenyl which is unfused or fused with arene or
heteroarene;
R.sup.27 is heteroarene which is unfused or fused with arene or
heteroarene;
R.sup.28 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.28A; R.sup.28A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.29 is heteroaryl or R.sup.29A; R.sup.29A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.30 is cycloalkyl or cycloalkenyl, each having one or two
CH.sub.2 moieties unreplaced or replaced with independently
selected O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and
one or two CH moieties unreplaced or replaced with N, and each of
which is unfused or fused with arene, heteroarene or R.sup.30A;
R.sup.30A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.31 and R.sup.31A are independently F, Cl, Br or alkyl or are
taken together and are C.sub.2-C.sub.5-spiroalkyl;
R.sup.32 is R.sup.33, C(O)R.sup.33 or C(O)OR.sup.33;
R.sup.33 is R.sup.34 or R.sup.35;
R.sup.34 is phenyl which is unfused or fused with aryl, heteroaryl
or R.sup.34A; R.sup.34A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.35 is alkyl which is unsubstituted or substituted with
R.sup.36;
R.sup.36 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.36A; R.sup.36A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.37 is R.sup.38, R.sup.39 or R.sup.40, each of which is
substituted with F, Cl, Br, I, R.sup.41, OR.sup.41, NHR.sup.41,
N(R.sup.41).sub.2, NHC(O)OR.sup.41, SR.sup.41, S(O)R.sup.41 or
SO.sub.2R.sup.41;
R.sup.38 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.38A; R.sup.38A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.39 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.39A; R.sup.39A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.40 is C.sub.3-C.sub.8-cycloalkyl or
C.sub.4-C.sub.8-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.40A; R.sup.40A
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.41 is R.sup.42, R.sup.43, R.sup.44 or R.sup.45;
R.sup.42 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.42A; R.sup.42A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.43 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.43A; R.sup.43A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.44 is C.sub.3-C.sub.9-cycloalkyl or
C.sub.4-C.sub.7-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.44A; R.sup.44A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.45 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two independently selected
R.sup.46, OR.sup.46, NHR.sup.46, N(R.sup.46).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.46, C(O)N(R.sup.46).sub.2, OH, (O), C(O)OH, N.sub.3,
CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
R.sup.46 is R.sup.47, R.sup.48 or R.sup.49;
R.sup.47 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.47A; R.sup.47A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.48 is heteroaryl or R.sup.48A; R.sup.48A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.49 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.49A; R.sup.49A is
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
wherein the moieties represented by R.sup.26 and R.sup.27 are
further substituted by one or two or three of independently
selected R.sup.50A, OR.sup.50A, SR.sup.50A, S(O)R.sup.50A,
SO.sub.2R.sup.50A or NHR.sup.50A;
R.sup.50A is R.sup.51A, R.sup.52A, R.sup.53A or R.sup.54A;
R.sup.51A is phenyl which is unfused or fused with benzene,
heteroarene or R.sup.51AA;
wherein R.sup.51AA is cycloalkane, cycloalkene or heterocycloalkane
heterocycloalkene,
R.sup.52A is heteroaryl;
R.sup.53A is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl; each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.53 AA wherein
R.sup.53AA is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.54A is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.55AA, OR.sup.55AA, SR.sup.55AA,
S(O)R.sup.55AA, SO.sub.2R.sup.55AA, NHR.sup.55AA,
N(R.sup.55AA).sub.2, C(O)R.sup.55AA, C(O)NH.sub.2,
C(O)NHR.sup.55AA, NHC(O)R.sup.55AA, NHSO.sub.2R.sup.55AA,
NHC(O)OR.sup.55AA, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.55AA,
SO.sub.2N(R.sup.55AA).sub.2, NHC(O)NH.sub.2, NHC(O)NHR.sup.55AA,
OH, (O), C(O)OH, (O), N.sub.3, CN, NH.sub.2, CF.sub.3, OCF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
R.sup.55AA is alkyl, alkenyl, alkynyl, phenyl or heteroaryl, or
R.sup.56A;
R.sup.56A is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N;
wherein moieties represented by R.sup.2R.sup.3R.sup.4, R.sup.6,
R.sup.6C, R.sup.8, R.sup.8A, R.sup.9, R.sup.10, R.sup.13, R.sup.14,
R.sup.15, R.sup.18, R.sup.19, R.sup.20, R.sup.23, R.sup.24,
R.sup.25, R.sup.26,R.sup.27, R.sup.28, R.sup.29, R.sup.30,
R.sup.34, R.sup.36, R.sup.38, R.sup.39, R.sup.40, R.sup.42,
R.sup.43, R.sup.44, R.sup.47, R.sup.48, and R.sup.49 are
independently unsubstituted, further unsubstituted, substituted or
further substituted with one or two or three or four or five
independently selected R.sup.50, OR.sup.50, SR.sup.50,
S(O)R.sup.50, SO.sub.2R.sup.50, C(O)R.sup.50, CO(O)R.sup.50,
OC(O)R.sup.50, OC(O)OR.sup.50, NH.sub.2, NHR.sup.50,
N(R.sup.50).sub.2, C(O)NH.sub.2, C(O)NHR.sup.50,
C(O)N(R.sup.50).sub.2, C(O)NHOH, C(O)NHOR.sup.50,
C(O)NHSO.sub.2R.sup.50, C(O)NR.sup.55SO.sub.2R.sup.50,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.50, SO.sub.2N(R.sup.50).sub.2,
CF.sub.3, CF.sub.2CF.sub.3, C(O)H, C(O)OH, C(N)NH.sub.2,
C(N)NHR.sup.50, C(N)N(R.sup.50).sub.2, OH, (O), CN, N.sub.3,
NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3,
F, Cl, Br or I substituents;
R.sup.50 is R.sup.51, R.sup.52, R.sup.53 or R.sup.54;
R.sup.51 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.51B; R.sup.51B is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.52 is heteroaryl;
R.sup.53 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.53B;
wherein R.sup.53B is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.54 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.55, OR.sup.55, SR.sup.55, S(O)R.sup.55,
SO.sub.2R.sup.55, NHR.sup.55, N(R.sup.55).sub.2, C(O)R.sup.55,
C(O)NH.sub.2, C(O)NHR.sup.55, NHC(O)R.sup.55, NHSO.sub.2R.sup.55,
NHC(O)OR.sup.55, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.55,
SO.sub.2N(R.sup.55).sub.2, NHC(O)NH.sub.2, NHC(O)NHR.sup.55, OH,
(O), C(O)OH, (O), N.sub.3, CN, NH.sub.2, CF.sub.3, OCF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
R.sup.55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or
R.sup.56;
wherein the alkyl, alkenyl, alkynyl are unsubstituted or
substituted with OCH.sub.3; and
R.sup.56 is C.sub.3-C.sub.8-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N.
Another embodiment of this invention pertains to compounds or
therapeutically acceptable salts, prodrugs or salts of prodrugs
thereof, which are useful as selective inhibitors of anti-apoptotic
Bcl-2 proteins, the compounds having Formula (II)
##STR00002## wherein
R.sup.100 is as described for substituents on R.sup.26; n is 0, 1,
2, or 3;
A.sup.1 is N or C(A.sup.2); one or two or three or each of A.sup.2,
B.sup.1, D.sup.1 and E.sup.1 are independently selected R.sup.1,
OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1, C(O)R.sup.1,
C(O)OR.sup.1, OC(O)R.sup.1, NHR.sup.1, N(R.sup.1).sub.2,
C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2, NHC(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)NHR.sup.1, NR.sup.1C(O)N(R.sup.1).sub.2,
SO.sub.2NHR.sup.1, SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NHSO.sub.2NHR.sup.1 or N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, and
the remainder are independently selected H, F, Cl, Br, I, CN,
CF.sub.3, C(O)OH, C(O)NH.sub.2 or C(O)OR.sup.1A; and
Y.sup.1 is H, CN, NO.sub.2, C(O)OH, F, Cl, Br, I, CF.sub.3,
OCF.sub.3, CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, R.sup.17,
OR.sup.17, C(O)R.sup.17, C(O)OR.sup.17, SR.sup.17, NH.sub.2,
NHR.sup.17, N(R.sup.17).sub.2, NHC(O)R.sup.17, C(O)NH.sub.2,
C(O)NHR.sup.17, C(O)N(R.sup.17).sub.2, NHS(O)R.sup.17 or
NHSO.sub.2R.sup.17; or
B.sup.1 and Y.sup.1, together with the atoms to which they are
attached, are imidazole or triazole; and
one or two or each of A.sup.2, D.sup.1 and E.sup.1 are
independently selected R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NHC(O)OR.sup.1, NHC(O)NHR.sup.1,
N(CH.sub.3)C(O)N(CH.sub.3)R.sup.1, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1 or
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, and the remainder are
independently selected H, F, Cl, Br, I, CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
R.sup.1 is R.sup.2, R.sup.3, R.sup.4 or R.sup.5;
R.sup.1A is C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl or
C.sub.3-C.sub.6-alkynyl;
R.sup.2 is phenyl which is unfused or fused with arene, heteroarene
or R.sup.2A; R.sup.2A is cycloalkane or heterocycloalkane;
R.sup.3 is heteroaryl which is unfused or fused with benzene,
heteroarene or R.sup.3A; R.sup.3A is cycloalkane or
heterocycloalkane;
R.sup.4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with arene,
heteroarene or R.sup.4A; R.sup.4A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.5 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.6, NC(R.sup.6A)(R.sup.6B), R.sup.7, OR.sup.7,
SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7, NHR.sup.7,
N(R.sup.7).sub.2, C(O)R.sup.7, C(O)NH.sub.2, C(O)NHR.sup.7,
NHC(O)R.sup.7, NHSO.sub.2R.sup.7, NHC(O)OR.sup.7, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2, NHC(O)NH.sub.2,
NHC(O)NHR.sup.7, NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NH.sub.2,
NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NHR.sup.1, OH, (O), C(O)OH,
(O), N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br
or I substituents;
R.sup.6 is C.sub.2-C.sub.5-spiroalkyl, each of which is
unsubstituted or substituted with OH, (O), N.sub.3, CN, CF.sub.3,
CF.sub.2CF.sub.3, F, Cl, Br, 1, NH.sub.2, NH(CH.sub.3) or
N(CH.sub.3).sub.2;
R.sup.6A and R.sup.6B are independently selected alkyl or, together
with the N to which they are attached, R.sup.6C;
R.sup.6C is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl or
piperidin-1-yl, each having one CH.sub.2 moiety unreplaced or
replaced with O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or
NH;
R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
R.sup.8 is phenyl which is unfused or fused with arene, heteroarene
or R.sup.8A;
R.sup.8A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.9 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.9A; R.sup.9A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.10 is C.sub.3-C.sub.10-cycloalkyl or
C.sub.4-C.sub.10-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.10A; R.sup.10A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.11 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.12, OR.sup.12, NHR.sup.12, N(R.sup.12).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.12, C(O)N(R.sup.12).sub.2, OH, (O),
C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl,
Br or I substituents;
R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16;
R.sup.13 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.13A; R.sup.13A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.14 is heteroaryl, each of which is unfused or fused with
arene, heteroarene or R.sup.14A; R.sup.14A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.15 is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene, each of which is unfused or fused with arene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.16 is alkyl, alkenyl or alkynyl;
R.sup.17 is R.sup.18, R.sup.19, R.sup.20 or R.sup.21;
R.sup.18 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.18A; R.sup.18A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.19 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.19A; R.sup.19A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.2 is C.sub.3-C.sub.10-cycloalkyl or
C.sub.4-C.sub.10-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.20A; R.sup.20A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.21 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.22, OR.sup.22, NHR.sup.22, N(R.sup.22).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.22, C(O)N(R.sup.22).sub.2, OH, (O),
C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl,
Br or I substituents;
R.sup.22 is R.sup.23, R.sup.24 or R.sup.25;
R.sup.23 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.23A; R.sup.23A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.24 is heteroarene which is unfused or fused with arene,
heteroarene or R.sup.24A; R.sup.24A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.25 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.25A; R.sup.25A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.30 is cycloalkyl or cycloalkenyl, each having one or two
CH.sub.2 moieties unreplaced or replaced with independently
selected O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and
one or two CH moieties unreplaced or replaced with N, and each of
which is unfused or fused with arene, heteroarene or R.sup.30A;
R.sup.30A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene; each of which is substituted with F, Cl, Br, I,
CH.sub.2R.sup.37, CH(R.sup.31)(R.sup.37),
C(R.sup.31)(R.sup.31A)(R.sup.37), C(O)R.sup.37, OR.sup.37,
SR.sup.37, S(O)R.sup.37, SO.sub.2R.sup.37, NHR.sup.37 or
N(R.sup.32)R.sup.37;
R.sup.31 and R.sup.31A are independently F, Cl, Br or alkyl or are
taken together and are C.sub.2-C.sub.5-spiroalkyl;
R.sup.32 is R.sup.33, C(O)R.sup.33 or C(O)OR.sup.33;
R.sup.33 is R.sup.34 or R.sup.35;
R.sup.34 is phenyl which is unfused or fused with aryl, heteroaryl
or R.sup.34A; R.sup.34A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.35 is alkyl which is unsubstituted or substituted with
R.sup.36;
R.sup.36 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.36A; R.sup.36A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.37 is R.sup.38, R.sup.39 or R.sup.40, each of which is
substituted with F, Cl, Br, I, R.sup.41, OR.sup.41, NHR.sup.41,
N(R.sup.41).sub.2, NHC(O)OR.sup.41, SR.sup.41, S(O)R.sup.41 or
SO.sub.2R.sup.41;
R.sup.38 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.38A; R.sup.38A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.39 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.39A; R.sup.39A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.40 is C.sub.3-C.sub.8-cycloalkyl or
C.sub.4-C.sub.8-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.40A; R.sup.40A
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.41 is R.sup.42, R.sup.43, R.sup.44 or R.sup.45;
R.sup.42 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.42A; R.sup.42A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.43 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.43A; R.sup.43A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.44 is C.sub.3-C.sub.9-cycloalkyl or
C.sub.4-C.sub.7-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.44A; R.sup.44A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.45 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two independently selected
R.sup.46, OR.sup.46, NHR.sup.46, N(R.sup.46).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.46, C(O)N(R.sup.46).sub.2, OH, (O), C(O)OH, N.sub.3,
CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
R.sup.46 is R.sup.47, R.sup.48 or R.sup.49;
R.sup.47 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.47A; R.sup.47A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.48 is heteroaryl or R.sup.48A; R.sup.48A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.49 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.49A; R.sup.49A is
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
wherein moieties represented by R.sup.2R.sup.3R.sup.4, R.sup.6,
R.sup.6C, R.sup.8, R.sup.8AR.sup.9, R.sup.10, R.sup.13, R.sup.14,
R.sup.15, R.sup.18, R.sup.19, R.sup.20, R.sup.23, R.sup.24,
R.sup.25, R.sup.26, R.sup.27, R.sup.28, R.sup.29,
R.sup.30,R.sup.34, R.sup.36, R.sup.38, R.sup.39, R.sup.40,R.sup.42,
R.sup.43, R.sup.44, R.sup.47, R.sup.48, and R.sup.49 are
independently unsubstituted, further unsubstituted, substituted or
further substituted with one or two or three or four or five
independently selected R.sup.50, OR.sup.50, SR.sup.50,
S(O)R.sup.50, SO.sub.2R.sup.50, C(O)R.sup.50, CO(O)R.sup.50,
OC(O)R.sup.50, OC(O)OR.sup.50, NH.sub.2, NHR.sup.50,
N(R.sup.50).sub.2, C(O)NH.sub.2, C(O)NHR.sup.50,
C(O)N(R.sup.50).sub.2, C(O)NHOH, C(O)NHOR.sup.50,
C(O)NHSO.sub.2R.sup.50, C(O)NR.sup.55SO.sub.2R.sup.50,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.50, SO.sub.2N(R.sup.50).sub.2,
CF.sub.3, CF.sub.2CF.sub.3, C(O)H, C(O)OH, C(N)NH.sub.2,
C(N)NHR.sup.50, C(N)N(R.sup.50).sub.2, OH, (O), CN, N.sub.3,
NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3,
F, Cl, Br or I substituents;
R.sup.50 is R.sup.51, R.sup.52, R.sup.53 or R.sup.54;
R.sup.51 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.51B; R.sup.51B is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.52 is heteroaryl;
R.sup.53 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.53B;
wherein R.sup.53B is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.54 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.55, OR.sup.55, SR.sup.55, S(O)R.sup.55,
SO.sub.2R.sup.55, NHR.sup.55, N(R.sup.55).sub.2, C(O)R.sup.55,
C(O)NH.sub.2, C(O)NHR.sup.55, NHC(O)R.sup.55, NHSO.sub.2R.sup.55,
NHC(O)OR.sup.55, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.55,
SO.sub.2N(R.sup.55).sub.2, NHC(O)NH.sub.2, NHC(O)NHR.sup.15, OH,
(O), C(O)OH, (O), N.sub.3, CN, NH.sub.2, CF.sub.3, OCF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
R.sup.55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or
R.sup.56;
wherein the alkyl, alkenyl, alkynyl are unsubstituted or
substituted with OCH.sub.3; and
R.sup.56 is C.sub.3-C.sub.8-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N.
Another embodiment of this invention pertains to compounds or
therapeutically acceptable salts, prodrugs or salts of prodrugs
thereof, which are useful as selective inhibitors of anti-apoptotic
Bcl-2 proteins, the compounds having Formula (III)
##STR00003## wherein
R.sup.10 is as described for substituents on R.sup.26;
n is 0, 1, 2, or 3;
A.sup.1 is N or C(A.sup.2);
one or two or three or each of A.sup.2, B.sup.1, D.sup.1 and
E.sup.1 are independently selected R.sup.1, OR.sup.1, SR.sup.1,
S(O)R.sup.1, SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1,
OC(O)R.sup.1, NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1,
C(O)N(R.sup.1).sub.2, NHC(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)NHR.sup.1, NR.sup.1C(O)N(R.sup.1).sub.2,
SO.sub.2NHR.sup.1, SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NHSO.sub.2NHR.sup.1 or N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, and
the remainder are independently selected H, F, Cl, Br, I, CN,
CF.sub.3, C(O)OH, C(O)NH.sub.2 or C(O)OR.sup.1A; and
Y.sup.1 is H, CN, NO.sub.2, C(O)OH, F, Cl, Br, I, CF.sub.3,
OCF.sub.3, CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, R.sup.17,
OR.sup.17, C(O)R.sup.17, C(O)OR.sup.17, SR.sup.17, NH.sub.2,
NHR.sup.17, N(R.sup.1).sub.2, NHC(O)R.sup.17, C(O)NH.sub.2,
C(O)NHR.sup.17, C(O)N(R.sup.17).sub.2, NHS(O)R.sup.17 or
NHSO.sub.2R.sup.17;
or
B.sup.1 and Y.sup.1, together with the atoms to which they are
attached, are imidazole or triazole; and one or two or each of
A.sup.2, D.sup.1 and E.sup.1 are independently selected R.sup.1,
OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1, C(O)R.sup.1,
C(O)OR.sup.1, OC(O)R.sup.1, NHR.sup.1, N(R.sup.1).sub.2,
C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2, NHC(O)R.sup.1, NHC(O)OR.sup.1,
NHC(O)NHR.sup.1, N(CH.sub.3)C(O)N(CH.sub.3)R.sup.1,
SO.sub.2NHR.sup.1, SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NHSO.sub.2NHR.sup.1 or N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, and
the remainder are independently selected H, F, Cl, Br, I, CF.sub.3,
C(O)OH, C(O)NH.sub.2 or C(O)OR.sup.1A,
R.sup.1 is R.sup.2, R.sup.3, R.sup.4 or R.sup.5;
R.sup.1a is C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl or
C.sub.3-C.sub.6-alkynyl;
R.sup.2 is phenyl which is unfused or fused with arene, heteroarene
or R.sup.2A; R.sup.2A is cycloalkane or heterocycloalkane;
R.sup.3 is heteroaryl which is unfused or fused with benzene,
heteroarene or R.sup.3A; R.sup.3A is cycloalkane or
heterocycloalkane;
R.sup.4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with arene,
heteroarene or R.sup.4A; R.sup.4A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.5 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.6, NC(R.sup.6A)(R.sup.6B), R.sup.7, OR.sup.7,
SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7, NHR.sup.7,
N(R.sup.7).sub.2, C(O)R.sup.7, C(O)NH.sub.2, C(O)NHR.sup.7,
NHC(O)R.sup.7, NHSO.sub.2R.sup.7, NHC(O)OR.sup.7, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2, NHC(O)NH.sub.2,
NHC(O)NHR.sup.7, NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NH.sub.2,
NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NHR.sup.7, OH, (O), C(O)OH,
(O), N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br
or I substituents;
R.sup.6 is C.sub.2-C.sub.5-spiroalkyl, each of which is
unsubstituted or substituted with OH, (O), N.sub.3, CN, CF.sub.3,
CF.sub.2CF.sub.3, F, Cl, Br, I, NH.sub.2, NH(CH.sub.3) or
N(CH.sub.3).sub.2;
R.sup.6A and R.sup.6B are independently selected alkyl or, together
with the N to which they are attached, R.sup.6C;
R.sup.6C is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl or
piperidin-1-yl, each having one CH.sub.2 moiety unreplaced or
replaced with O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or
NH;
R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
R.sup.8 is phenyl which is unfused or fused with arene, heteroarene
or R.sup.8A;
R.sup.8A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.9 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.9A; R.sup.9A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.10 is C.sub.3-C.sub.10-cycloalkyl or
C.sub.4-C.sub.10-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.10A; R.sup.10A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.11 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.12, OR.sup.12, NHR.sup.12, N(R.sup.1).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.12, C(O)N(R.sup.2).sub.2, OH, (O),
C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl,
Br or I substituents;
R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16;
R.sup.13 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.13A; R.sup.13A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.14 is heteroaryl, each of which is unfused or fused with
arene, heteroarene or R.sup.14A;
R.sup.14A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.15 is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene, each of which is unfused or fused with arene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.16 is alkyl, alkenyl or alkynyl;
R.sup.17 is R.sup.18, R.sup.19, R.sup.20 or R.sup.21;
R.sup.18 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.18A; R.sup.18A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.19 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.19A; R.sup.19A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.20 is C.sub.3-C.sub.10-cycloalkyl or
C.sub.4-C.sub.10-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.20A; R.sup.20A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.2 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.22, OR.sup.22, NHR.sup.22, N(R.sup.22).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.22, C(O)N(R.sup.22).sub.2, OH, (O),
C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl,
Br or I substituents;
R.sup.22 is R.sup.3, R.sup.24 or R.sup.25;
R.sup.23 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.23A; R.sup.23A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.24 is heteroarene which is unfused or fused with arene,
heteroarene or R.sup.24A; R.sup.24A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.25 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.25A; R.sup.25A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.30 is cycloalkyl or cycloalkenyl, each having one or two
CH.sub.2 moieties unreplaced or replaced with independently
selected O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and
one or two CH moieties unreplaced or replaced with N, and each of
which is unfused or fused with arene, heteroarene or R.sup.30A;
R.sup.30A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene; each of which is substituted with F, Cl, Br, I,
CH.sub.2R.sup.37, CH(R.sup.31)(R.sup.37),
C(R.sup.31)(R.sup.31A)(R.sup.37), C(O)R.sup.37, OR.sup.37,
SR.sup.37, S(O)R.sup.37, SO.sub.2R.sup.37, NHR.sup.37 or
N(R.sup.32)R.sup.37;
R.sup.31 and R.sup.31A are independently F, Cl, Br or alkyl or are
taken together and are C.sub.2-C.sub.5-spiroalkyl;
R.sup.32 is R.sup.33, C(O)R.sup.33 or C(O)OR.sup.33;
R.sup.33 is R.sup.34 or R.sup.35;
R.sup.34 is phenyl which is unfused or fused with aryl, heteroaryl
or R.sup.34A; R.sup.34A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.35 is alkyl which is unsubstituted or substituted with
R.sup.36;
R.sup.36 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.36A; R.sup.36A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.37 is R.sup.38, R.sup.39 or R.sup.40, each of which is
substituted with F, Cl, Br, I, R.sup.41, OR.sup.41, NHR.sup.41,
N(R.sup.41).sub.2, NHC(O)OR.sup.41, SR.sup.41, S(O)R.sup.41 or
SO.sub.2R.sup.41;
R.sup.38 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.38A; R.sup.38A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.39 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.39A; R.sup.39A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.40 is C.sub.3-C.sub.8-cycloalkyl or
C.sub.4-C.sub.8-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.40A; R.sup.40A
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.41 is R.sup.42, R.sup.43, R.sup.44 or R.sup.45;
R.sup.42 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.42A; R.sup.42A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.43 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.43A; R.sup.43A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.44 is C.sub.3-C.sub.9-cycloalkyl or
C.sub.4-C.sub.7-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.44A; R.sup.44A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.45 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two independently selected
R.sup.46, OR.sup.46, NHR.sup.46, N(R.sup.46).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.46, C(O)N(R.sup.46).sub.2, OH, (O), C(O)OH, N.sub.3,
CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
R.sup.46 is R.sup.47, R.sup.48 or R.sup.49;
R.sup.47 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.47A; R.sup.47A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.48 is heteroaryl or R.sup.48A; R.sup.48A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.49 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.49A; R.sup.49A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
wherein moieties represented by R.sup.2R.sup.3R.sup.4, R.sup.6,
R.sup.6C, R.sup.8, R.sup.8AR.sup.9, R.sup.10, R.sup.13, R.sup.14,
R.sup.15, R.sup.18, R.sup.19, R.sup.20, R.sup.23, R.sup.24,
R.sup.2, R.sup.26, R.sup.27, R.sup.28, R.sup.29, R.sup.30,
R.sup.34, R.sup.36, R.sup.38, R.sup.39, R.sup.40, R.sup.42,
R.sup.43, R.sup.44, R.sup.47, R.sup.48, and R.sup.49 are
independently unsubstituted, further unsubstituted, substituted or
further substituted with one or two or three or four or five
independently selected R.sup.50, OR.sup.50, SR.sup.50,
S(O)R.sup.50, SO.sub.2R.sup.50, C(O)R.sup.50, CO(O)R.sup.50,
OC(O)R.sup.50, OC(O)OR.sup.50, NH.sub.2, NHR.sup.50,
N(R.sup.50).sub.2, C(O)NH.sub.2, C(O)NHR.sup.50,
C(O)N(R.sup.50).sub.2, C(O)NHOH, C(O)NHOR.sup.50,
C(O)NHSO.sub.2R.sup.50, C(O)NR.sup.55SO.sub.2R.sup.50,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.50, SO.sub.2N(R.sup.50).sub.2,
CF.sub.3, CF.sub.2CF.sub.3, C(O)H, C(O)OH, C(N)NH.sub.2,
C(N)NHR.sup.50, C(N)N(R.sup.50).sub.2, OH, (O), CN, N.sub.3,
NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3,
F, Cl, Br or I substituents;
R.sup.50 is R.sup.51, R.sup.52, R.sup.53 or R.sup.54;
R.sup.51 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.51B; R.sup.51B is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.52 is heteroaryl;
R.sup.53 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.53B;
wherein R.sup.53B is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.54 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.55, OR.sup.55, SR.sup.55, S(O)R.sup.55,
SO.sub.2R.sup.55, NHR.sup.55, N(R.sup.55).sub.2, C(O)R.sup.55,
C(O)NH.sub.2, C(O)NHR.sup.55, NHC(O)R.sup.55, NHSO.sub.2R.sup.55,
NHC(O)OR.sup.55, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.55,
SO.sub.2N(R.sup.55).sub.2, NHC(O)NH.sub.2, NHC(O)NHR.sup.55, OH,
(O), C(O)OH, (O), N.sub.3, CN, NH.sub.2, CF.sub.3, OCF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
R.sup.55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or
R.sup.56;
wherein the alkyl, alkenyl, alkynyl are unsubstituted or
substituted with OCH.sub.3; and
R.sup.56 is C.sub.3-C.sub.8-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N.
Another embodiment of this invention pertains to compounds or
therapeutically acceptable salts, prodrugs or salts of prodrugs
thereof, which are useful as selective inhibitors of anti-apoptotic
Bcl-2 proteins, the compounds having Formula (IV)
##STR00004## wherein
R.sup.100 is as described for substituents on R.sup.26;
n is 0, 1, 2, or 3;
A.sup.1 is N or C(A.sup.2);
one or two or three or each of A.sup.2, B.sup.1, D and E.sup.1 are
independently selected R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NHC(O)OR.sup.1, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1 or
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, and the remainder are
independently selected H, F, Cl, Br, I, CN, CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A; and
Y.sup.1 is H, CN, NO.sub.2, C(O)OH, F, Cl, Br, I, CF.sub.3,
OCF.sub.3, CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, R.sup.17,
OR.sup.17, C(O)R.sup.17, C(O)OR.sup.17, SR.sup.17, NH.sub.2,
NHR.sup.17, N(R.sup.17).sub.2, NHC(O)R.sup.17, C(O)NH.sub.2,
C(O)NHR.sup.17, C(O)N(R.sup.17).sub.2, NHS(O)R.sup.17 or
NHSO.sub.2R.sup.17;
or
B.sup.1 and Y.sup.1, together with the atoms to which they are
attached, are imidazole or triazole; and one or two or each of
A.sup.2, D.sup.1 and E.sup.1 are independently selected R.sup.1,
OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1, C(O)R.sup.1,
C(O)OR.sup.1, OC(O)R.sup.1, NHR.sup.1, N(R.sup.1).sub.2,
C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2, NHC(O)R.sup.1, NHC(O)OR.sup.1,
NHC(O)NHR.sup.1, N(CH.sub.3)C(O)N(CH.sub.3)R.sup.1,
SO.sub.2NHR.sup.1, SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NHSO.sub.2NHR.sup.1 or N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, and
the remainder are independently selected H, F, Cl, Br, I, CF.sub.3,
C(O)OH, C(O)NH.sub.2 or C(O)OR.sup.1A;
R.sup.1 is R.sup.2, R.sup.3, R.sup.4 or R.sup.5;
R.sup.1A is C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl or
C.sub.3-C.sub.6-alkynyl;
R.sup.2 is phenyl which is unfused or fused with arene, heteroarene
or R.sup.2A; R.sup.2A is cycloalkane or heterocycloalkane;
R.sup.3 is heteroaryl which is unfused or fused with benzene,
heteroarene or R.sup.3A; R.sup.3A is cycloalkane or
heterocycloalkane;
R.sup.4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with arene,
heteroarene or R.sup.4A; R.sup.4A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.5 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.6, NC(R.sup.6A)(R.sup.6B), R.sup.7, OR.sup.7,
SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7, NHR.sup.7,
N(R.sup.7).sub.2, C(O)R.sup.7, C(O)NH.sub.2, C(O)NHR.sup.7,
NHC(O)R.sup.7, NHSO.sub.2R.sup.7, NHC(O)OR.sup.7, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2, NHC(O)NH.sub.2,
NHC(O)NHR.sup.7, NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NH.sub.2,
NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NHR.sup.1, OH, (O), C(O)OH,
(O), N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br
or I substituents;
R.sup.6 is C.sub.2-C.sub.5-spiroalkyl, each of which is
unsubstituted or substituted with OH, (O), N.sub.3, CN, CF.sub.3,
CF.sub.2CF.sub.3, F, Cl, Br, I, NH.sub.2, NH(CH.sub.3) or
N(CH.sub.3).sub.2;
R.sup.6A and R.sup.6B are independently selected alkyl or, together
with the N to which they are attached, R.sup.6C;
R.sup.6C is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl or
piperidin-1-yl, each having one CH.sub.2 moiety unreplaced or
replaced with O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or
NH;
R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
R.sup.8 is phenyl which is unfused or fused with arene, heteroarene
or R.sup.8A;
R.sup.8A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.9 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.9A; R.sup.9A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.10 is C.sub.3-C.sub.10-cycloalkyl or
C.sub.4-C.sub.10-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.10A; R.sup.10A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.11 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.12, OR.sup.12, NHR.sup.12, N(R.sup.12).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.12, C(O)N(R.sup.12).sub.2, OH, (O),
C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl,
Br or I substituents;
R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16;
R.sup.13 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.13A; R.sup.13A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.14 is heteroaryl, each of which is unfused or fused with
arene, heteroarene or R.sup.14A; R.sup.14A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.5 is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene, each of which is unfused or fused with arene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.16 is alkyl, alkenyl or alkynyl;
R.sup.17 is R.sup.18, R.sup.19, R.sup.20 or R.sup.21;
R.sup.18 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.18A; R.sup.18A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.19 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.19A; R.sup.19A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.20 is C.sub.3-C.sub.10-cycloalkyl or
C.sub.4-C.sub.10-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.20A; R.sup.20A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.21 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.22, OR.sup.22, NHR.sup.22, N(R.sup.22).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.22, C(O)N(R.sup.22).sub.2, OH, (O),
C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl,
Br or I substituents;
R.sup.22 is R.sup.23, R.sup.24 or R.sup.25;
R.sup.23 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.23A; R.sup.23A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.24 is heteroarene which is unfused or fused with arene,
heteroarene or R.sup.24A; R.sup.24A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.25 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.25A; R.sup.25A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.30 is cycloalkyl or cycloalkenyl, each having one or two
CH.sub.2 moieties unreplaced or replaced with independently
selected O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and
one or two CH moieties unreplaced or replaced with N, and each of
which is unfused or fused with arene, heteroarene or R.sup.30A;
R.sup.30A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene; each of which is substituted with F, Cl, Br, I,
CH.sub.2R.sup.37, CH(R.sup.31)(R.sup.37),
C(R.sup.31)(R.sup.31A)(R.sup.37), C(O)R.sup.37, OR.sup.37,
SR.sup.37, S(O)R.sup.37, SO.sub.2R.sup.37, NHR.sup.37 or
N(R.sup.32)R.sup.37;
R.sup.31 and R.sup.31A are independently F, Cl, Br or alkyl or are
taken together and are C.sub.2-C.sub.5-spiroalkyl;
R.sup.32 is R.sup.33, C(O)R.sup.33 or C(O)OR.sup.33;
R.sup.33 is R.sup.34 or R.sup.35;
R.sup.34 is phenyl which is unfused or fused with aryl, heteroaryl
or R.sup.34A; R.sup.34A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.35 is alkyl which is unsubstituted or substituted with
R.sup.36;
R.sup.36 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.36A; R.sup.36A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.37 is R.sup.38, R.sup.39 or R.sup.40, each of which is
substituted with F, Cl, Br, I, R.sup.41, OR.sup.41, NHR.sup.41,
N(R.sup.41).sub.2, NHC(O)OR.sup.41, SR.sup.41, S(O)R.sup.41 or
SO.sub.2R.sup.41;
R.sup.38 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.38A; R.sup.38A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.39 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.39A; R.sup.39A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.40 is C.sub.3-C.sub.8-cycloalkyl or
C.sub.4-C.sub.8-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.40A; R.sup.40A
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.41 is R.sup.42, R.sup.43, R.sup.44 or R.sup.45;
R.sup.42 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.42A; R.sup.42A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.43 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.43A; R.sup.43A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.44 is C.sub.3-C.sub.9-cycloalkyl or
C.sub.4-C.sub.7-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.44A; R.sup.44A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.45 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two independently selected
R.sup.46, OR.sup.46, NHR.sup.46, N(R.sup.46).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.46, C(O)N(R.sup.46).sub.2, OH, (O), C(O)OH, N.sub.3,
CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
R.sup.46 is R.sup.47, R.sup.48 or R.sup.49;
R.sup.47 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.47A; R.sup.47A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.48 is heteroaryl or R.sup.48A; R.sup.48A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.49 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.49A; R.sup.49A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
wherein moieties represented by R.sup.2R.sup.3R.sup.4, R.sup.6,
R.sup.6C, R.sup.8, R.sup.8AR.sup.9, R.sup.10, R.sup.13, R.sup.14,
R.sup.15, R.sup.18, R.sup.19, R.sup.20, R.sup.23, R.sup.24,
R.sup.25, R.sup.26, R.sup.27, R.sup.28, R.sup.29, R.sup.30,
R.sup.34, R.sup.36, R.sup.38, R.sup.39, R.sup.40, R.sup.42,
R.sup.43, R.sup.44, R.sup.47, R.sup.48, and R.sup.49 are
independently unsubstituted, further unsubstituted, substituted or
further substituted with one or two or three or four or five
independently selected R.sup.50, OR.sup.50, SR.sup.50,
S(O)R.sup.50, SO.sub.2R.sup.50, C(O)R.sup.50, CO(O)R.sup.50,
OC(O)R.sup.50, OC(O)OR.sup.50, NH.sub.2, NHR.sup.50,
N(R.sup.50).sub.2, C(O)NH.sub.2, C(O)NHR.sup.50,
C(O)N(R.sup.50).sub.2, C(O)NHOH, C(O)NHOR.sup.50,
C(O)NHSO.sub.2R.sup.50, C(O)NR.sup.55SO.sub.2R.sup.50,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.50, SO.sub.2N(R.sup.50).sub.2,
CF.sub.3, CF.sub.2CF.sub.3, C(O)H, C(O)OH, C(N)NH.sub.2,
C(N)NHR.sup.50, C(N)N(R.sup.50).sub.2, OH, (O), CN, N.sub.3,
NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3,
F, Cl, Br or I substituents;
R.sup.50 is R.sup.51, R.sup.52, R.sup.53 or R.sup.54;
R.sup.51 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.51B; R.sup.51B is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.52 is heteroaryl;
R.sup.53 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.53B;
wherein R.sup.53B is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.54 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.55, OR.sup.55, SR.sup.55, S(O)R.sup.55,
SO.sub.2R.sup.55, NHR.sup.55, N(R.sup.55).sub.2, C(O)R.sup.55,
C(O)NH.sub.2, C(O)NHR.sup.55, NHC(O)R.sup.15, NHSO.sub.2R.sup.55,
NHC(O)OR.sup.55, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.55,
SO.sub.2N(R.sup.55).sub.2, NHC(O)NH.sub.2, NHC(O)NHR.sup.15, OH,
(O), C(O)OH, (O), N.sub.3, CN, NH.sub.2, CF.sub.3, OCF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
R.sup.55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or
R.sup.56;
wherein the alkyl, alkenyl, alkynyl are unsubstituted or
substituted with OCH.sub.3; and
R.sup.56 is C.sub.3-C.sub.8-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N.
Another embodiment of this invention pertains to compounds or
therapeutically acceptable salts, prodrugs or salts of prodrugs
thereof, which are useful as selective inhibitors of anti-apoptotic
Bcl-2 proteins, the compounds having Formula (V)
##STR00005## wherein
R.sup.10 is as described for substituents on R.sup.26;
n is 0, 1, 2, or 3;
A.sup.1 is N or C(A.sup.2);
one or two or three or each of A.sup.2, B.sup.1, D.sup.1 and
E.sup.1 are independently selected R.sup.1, OR.sup.1, SR.sup.1,
S(O)R.sup.1, SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1,
OC(O)R.sup.1, NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1,
C(O)N(R.sup.1).sub.2, NHC(O)R.sup.1, NHC(O)OR,
NR.sup.1C(O)NHR.sup.1, NR.sup.1C(O)N(R.sup.1).sub.2,
SO.sub.2NHR.sup.1, SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NHSO.sub.2NHR.sup.1 or N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, and
the remainder are independently selected H, F, Cl, Br, I, CN,
CF.sub.3, C(O)OH, C(O)NH.sub.2 or C(O)OR.sup.1A; and
Y.sup.1 is H, CN, NO.sub.2, C(O)OH, F, Cl, Br, I, CF.sub.3,
OCF.sub.3, CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, R.sup.17,
OR.sup.17, C(O)R.sup.17, C(O)OR.sup.17, SR.sup.17, NH.sub.2,
NHR.sup.17, N(R.sup.1).sub.2, NHC(O)R.sup.17, C(O)NH.sub.2,
C(O)NHR.sup.17, C(O)N(R.sup.17).sub.2, NHS(O)R.sup.17 or
NHSO.sub.2R.sup.17;
or
B.sup.1 and Y.sup.1, together with the atoms to which they are
attached, are imidazole or triazole; and
one or two or each of A.sup.2, D.sup.1 and E.sup.1 are
independently selected R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NHC(O)OR.sup.1, NHC(O)NHR.sup.1,
N(CH.sub.3)C(O)N(CH.sub.3)R.sup.1, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1 or
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, and the remainder are
independently selected H, F, Cl, Br, I, CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
R.sup.1 is R.sup.2, R.sup.3, R.sup.4 or R.sup.5;
R.sup.1A is C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl or
C.sub.3-C.sub.6-alkynyl;
R.sup.2 is phenyl which is unfused or fused with arene, heteroarene
or R.sup.2A; R.sup.2A is cycloalkane or heterocycloalkane;
R.sup.3 is heteroaryl which is unfused or fused with benzene,
heteroarene or R.sup.3A; R.sup.3A is cycloalkane or
heterocycloalkane;
R.sup.4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with arene,
heteroarene or R.sup.4A; R.sup.4A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.5 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.6, NC(R.sup.6A)(R.sup.6B), R.sup.7, OR.sup.7,
SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7, NHR.sup.7,
N(R.sup.7).sub.2, C(O)R.sup.7, C(O)NH.sub.2, C(O)NHR.sup.7,
NHC(O)R.sup.7, NHSO.sub.2R.sup.7, NHC(O)OR.sup.7, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2, NHC(O)NH.sub.2,
NHC(O)NHR.sup.7, NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NH.sub.2,
NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NHR.sup.7, OH, (O), C(O)OH,
(O), N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br
or I substituents;
R.sup.6 is C.sub.2-C.sub.5-spiroalkyl, each of which is
unsubstituted or substituted with OH, (O), N.sub.3, CN, CF.sub.3,
CF.sub.2CF.sub.3, F, Cl, Br, I, NH.sub.2, NH(CH.sub.3) or
N(CH.sub.3).sub.2;
R.sup.6A and R.sup.6B are independently selected alkyl or, together
with the N to which they are attached, R.sup.6C;
R.sup.6C is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl or
piperidin-1-yl, each having one CH.sub.2 moiety unreplaced or
replaced with O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or
NH;
R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
R.sup.8 is phenyl which is unfused or fused with arene, heteroarene
or R.sup.8A;
R.sup.8A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.9 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.9A; R.sup.9A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.10 is C.sub.3-C.sub.10-cycloalkyl or
C.sub.4-C.sub.10-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.10A; R.sup.10A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.11 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.12, OR.sup.12, NHR.sup.12, N(R.sup.12).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.2, C(O)N(R.sup.12).sub.2, OH, (O),
C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl,
Br or I substituents;
R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16;
R.sup.13 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.13A; R.sup.13A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.14 is heteroaryl, each of which is unfused or fused with
arene, heteroarene or R.sup.14A;
R.sup.14A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.15 is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene, each of which is unfused or fused with arene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.16 is alkyl, alkenyl or alkynyl;
R.sup.17 is R.sup.18, R.sup.19, R.sup.20 or R.sup.21;
R.sup.18 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.18A; R.sup.18A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.19 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.19A; R.sup.9A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.20 is C.sub.3-C.sub.10-cycloalkyl or
C.sub.4-C.sub.10-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.20A; R.sup.20A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.21 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.22, OR.sup.21, NHR.sup.22, N(R.sup.22).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.22, C(O)N(R.sup.22).sub.2, OH, (O),
C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl,
Br or I substituents;
R.sup.22 is R.sup.23, R.sup.24 or R.sup.25;
R.sup.23 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.23A; R.sup.23A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.24 is heteroarene which is unfused or fused with arene,
heteroarene or R.sup.24A; R.sup.24A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.25 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.25A; R.sup.25A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.30 is cycloalkyl or cycloalkenyl, each having one or two
CH.sub.2 moieties unreplaced or replaced with independently
selected O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and
one or two CH moieties unreplaced or replaced with N, and each of
which is unfused or fused with arene, heteroarene or R.sup.30A;
R.sup.30A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene; each of which is substituted with F, Cl, Br, I,
CH.sub.2R.sup.37, CH(R.sup.31)(R.sup.37),
C(R.sup.31)(R.sup.31A)(R.sup.37), C(O)R.sup.37, OR.sup.37,
SR.sup.37, S(O)R.sup.37, SO.sub.2R.sup.37, NHR.sup.37 or
N(R.sup.32)R.sup.37;
R.sup.31 and R.sup.31A are independently F, Cl, Br or alkyl or are
taken together and are C.sub.2-C.sub.5-spiroalkyl;
R.sup.32 is R.sup.33, C(O)R.sup.33 or C(O)OR.sup.33;
R.sup.33 is R.sup.34 or R.sup.35;
R.sup.34 is phenyl which is unfused or fused with aryl, heteroaryl
or R.sup.34A; R.sup.34A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.35 is alkyl which is unsubstituted or substituted with
R.sup.36;
R.sup.36 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.36A; R.sup.36A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.37 is R.sup.38, R.sup.39 or R.sup.40, each of which is
substituted with F, Cl, Br, I, R.sup.41, OR.sup.41, NHR.sup.41,
N(R.sup.41).sub.2, NHC(O)OR.sup.41, SR.sup.41, S(O)R.sup.41 or
SO.sub.2R.sup.41;
R.sup.38 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.38A; R.sup.38A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.39 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.39A; R.sup.39A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.40 is C.sub.3-C.sub.8-cycloalkyl or
C.sub.4-C.sub.8-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.40A; R.sup.40A
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.41 is R.sup.42, R.sup.43, R.sup.44 or R.sup.45;
R.sup.42 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.42A; R.sup.42A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.43 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.43A; R.sup.43A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.44 is C.sub.3-C.sub.9-cycloalkyl or
C.sub.4-C.sub.7-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.44A; R.sup.44A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.45 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two independently selected
R.sup.46, OR.sup.46, NHR.sup.46, N(R.sup.46).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.46, C(O)N(R.sup.46).sub.2, OH, (O), C(O)OH, N.sub.3,
CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
R.sup.46 is R.sup.47, R.sup.48 or R.sup.49;
R.sup.47 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.47A; R.sup.47A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.48 is heteroaryl or R.sup.48A; R.sup.48A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.49 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.49A; R.sup.49A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
wherein moieties represented by R.sup.2R.sup.3R.sup.4, R.sup.6,
R.sup.6C, R.sup.8, R.sup.8AR.sup.9, R.sup.10, R.sup.13, R.sup.14,
R.sup.15, R.sup.18, R.sup.19, R.sup.20, R.sup.23, R.sup.24,
R.sup.25, R.sup.26, R.sup.27, R.sup.28, R.sup.29, R.sup.30,
R.sup.34, R.sup.36, R.sup.38, R.sup.39, R.sup.40, R.sup.42,
R.sup.43, R.sup.44, R.sup.47, R.sup.48, and R.sup.49 are
independently unsubstituted, further unsubstituted, substituted or
further substituted with one or two or three or four or five
independently selected R.sup.50, OR.sup.50, SR.sup.50,
S(O)R.sup.50, SO.sub.2R.sup.50, C(O)R.sup.50, CO(O)R.sup.50,
OC(O)R.sup.50, OC(O)OR.sup.50, NH.sub.2, NHR.sup.50,
N(R.sup.50).sub.2, C(O)NH.sub.2, C(O)NHR.sup.50,
C(O)N(R.sup.50).sub.2, C(O)NHOH, C(O)NHOR.sup.50,
C(O)NHSO.sub.2R.sup.50, C(O)NR.sup.55SO.sub.2R.sup.50,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.50, SO.sub.2N(R.sup.50).sub.2,
CF.sub.3, CF.sub.2CF.sub.3, C(O)H, C(O)OH, C(N)NH.sub.2,
C(N)NHR.sup.50, C(N)N(R.sup.50).sub.2, OH, (O), CN, N.sub.3,
NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3,
F, Cl, Br or I substituents;
R.sup.50 is R.sup.51, R.sup.52, R.sup.53 or R.sup.54;
R.sup.51 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.51B; R.sup.51B is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.52 is heteroaryl;
R.sup.53 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.53B;
wherein R.sup.53B is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.54 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.55, OR.sup.55, SR.sup.55, S(O)R.sup.55,
SO.sub.2R.sup.55, NHR.sup.55, N(R.sup.55).sub.2, C(O)R.sup.55,
C(O)NH.sub.2, C(O)NHR.sup.55, NHC(O)R.sup.55, NHSO.sub.2R.sup.55,
NHC(O)OR.sup.55, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.55,
SO.sub.2N(R.sup.55).sub.2, NHC(O)NH.sub.2, NHC(O)NHR.sup.55, OH,
(O), C(O)OH, (O), N.sub.3, CN, NH.sub.2, CF.sub.3, OCF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
R.sup.55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or
R.sup.56;
wherein the alkyl, alkenyl, alkynyl are unsubstituted or
substituted with OCH.sub.3; and
R.sup.56 is C.sub.3-C.sub.8-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N.
Another embodiment pertains to compounds of Formula (I), Formula
(TI), Formula (III), Formula (IV), or Formula (V) wherein A.sup.1
is C(A.sup.2); and A.sup.2 is H.
Another embodiment pertains to compounds of Formula (I), Formula
(II), Formula (III), Formula (IV), or Formula (V) wherein A.sup.1
is C(A.sup.2); A.sup.2 is H; and B.sup.1 is NHR.sup.1.
Another embodiment pertains to compounds of Formula (I), Formula
(II), Formula (III), Formula (IV), or Formula (V) wherein A.sup.1
is C(A.sup.2); A.sup.2 is H; B.sup.1 is NHR.sup.1; and D.sup.1 is
H.
Another embodiment pertains to compounds of Formula (I), Formula
(II), Formula (III), Formula (IV), or Formula (V) wherein A.sup.1
is C(A.sup.2); A.sup.2 is H; B.sup.1 is NHR.sup.1; D.sup.1 is H;
and E.sup.1 is H.
Another embodiment pertains to compounds of Formula (I), Formula
(II), Formula (III), Formula (IV), or Formula (V) wherein A.sup.1
is C(A.sup.2); A.sup.2 is H; B.sup.1 is NHR.sup.1; D.sup.1 is H;
E.sup.1 is H; and Y.sup.1 is NO.sub.2.
Still another embodiment pertains to compounds having Formula I
which are
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide-
; benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((-
4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;
2-(benzyloxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)--
N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benza-
mide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nit-
ro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(2-phenylet-
hoxy)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenylthio)benz-
amide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(pheny-
lthio)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzam-
ide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3--
morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(phenylthio)benzamid-
e;
4-(4-((4'-chloro-1,1-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-
-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenylsulfonyl-
)benzamide;
4-(4-((4'-chloro-1,1-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(-
(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenylsulfinyl)b-
enzamide;
2-benzyl-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1--
yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)b-
enzamide;
2-benzyl-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1--
yl)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide-
;
2-(4-((4-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morp-
holin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(2
phenylethyl)benzamide;
2-(benzylamino)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl-
)-N-((3-nitro-4-2-anilino-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sul-
fonyl)benzamide;
2-anilino-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((-
4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-methoxy-N-((-
3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide-
;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazi-
n-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-ph-
enoxybenzamide;
4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-phe-
noxybenzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indazol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitr-
ophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indazol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitr-
ophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(1,-
2,3,4-tetrahydroquinolin-6-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(1,-
2,3,4-tetrahydroquinolin-6-yloxy)benzamide;
4-(4-((4'-chloro-4-(pyrrolidin-1-ylmethyl)-1,1-biphenyl-2-yl)methyl)piper-
azin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylme-
thyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl-
methyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((1-cyclopentylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)--
2-(1H-indol-5-yloxy)benzamide
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)-3-isobutylpiperazin-1-yl)-N-(-
(3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-pheno-
xybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(2,4-dio-
xo-3-azabicyclo(3.2.0)hept-3-yl)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(4-methy-
l-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)sulfonyl)-2-phenoxybenzami-
de;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(3,3--
dimethyl-2-oxoazetidin-1-yl)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(4-nitro--
2H-1,2,3-triazol-2-yl)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((-
2-(2-piperidin-1-ylethoxy)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-((((1-et-
hylpyrrolidin-2-yl)methyl)amino)carbonyl)-4-methoxyphenyl)sulfonyl)-2-phen-
oxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1-naphthylo-
xy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)b-
enzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2--
naphthyloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)s-
ulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morp-
holin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-naphthyloxy)benzamide-
;
4-(4-((4'-chloro-1,1-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-naphthylo-
xy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulf-
onyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(-
(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(quinolin-7-yloxy-
)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(quinolin-6-ylox-
y)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5--
yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfony-
l)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(isoquinolin-
-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulf-
onyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(isoquinolin-5-yloxy)be-
nzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4--
((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(quinolin-6-ylo-
xy)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benza-
mide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-ind-
ol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)su-
lfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benza-
mide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-
-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-6-yloxy)-
benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(i-
soquinolin-7-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)su-
lfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(isoquinolin-7-yloxy)be-
nzamide;
4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)p-
iperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)--
3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1-
H-indol-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrop-
henyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1-
H-indol-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrop-
henyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrop-
henyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1-
H-indol-4-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1-
H-indol-4-yloxy)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4--
yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzam-
ide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indo-
l-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)be-
nzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4--
methoxyphenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-methylph-
enyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5--
yloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino-3-((trifluoromethyl)su-
lfonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4--
yloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)s-
ulfonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-2-(-
H-indol-5-yloxy)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4--
yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-((trifluoromethyl)sulfonyl)-
phenyl)sulfonyl)benzamide;
N-((3-((chloro(difluoro)methyl)sulfonyl)-4-((3-(dimethylamino)propyl)amin-
o)phenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-y-
l)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;
2-(1H-indol-4-yloxy)-4-(4-((2-(4-methoxyphenyl)-4,4-dimethylcyclohex-1-en-
-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino-
)phenyl)sulfonyl)benzamide;
4-(4-((4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)cyclohex-1-en-1-yl)methy-
l)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpr-
opyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4,4-dimethyl-2-(4-(trifluoromethoxy)phenyl)cyclohex-1-en-1-yl)meth-
yl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylp-
ropyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4,4-dimethyl-2-(3-(trifluoromethyl)phenyl)cyclohex-1-en-1-yl)methy-
l)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpr-
opyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((2-(3-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)-
phenyl)sulfonyl)benzamide;
4-(4-((2-(4-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)-
phenyl)sulfonyl)benzamide;
N-((3-((chloro(difluoro)methyl)sulfonyl)-4-((1-methylpiperidin-4-yl)amino-
)phenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl-
)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H--
indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfony-
l)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((I-methylpiperidin-4-yl)amino)-3-((trif-
luoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenoxymethyl)b-
enzamide;
4-(4-((4'-chloro-1,1-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4--
((3-morpholin-4-ylpropyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(pyridin-3-yloxy-
)benzamide;
4-(4-((4'-chloro-1,1-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(pyridin-3-yl-
oxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamid-
e;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(((1R)-
-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfo-
nyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(pyridin-4-yloxy-
)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morp-
holin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(pyridin-3-yloxy)benzami-
de;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-m-
orpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(pyridin-4-yloxy)benz-
amide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((-
2-(4-methylpiperazin-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybe-
nzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4--
((3-(4-methylpiperazin-1-yl)propyl)amino)-3-nitrophenyl)sulfonyl)-2-phenox-
ybenzamide;
4-(4-((4'-chloro-1,1-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dime-
thylamino)propyl)(methyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide-
;
4-(4-((4'-chloro-1,1-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(((1-met-
hylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide-
;
4-(4-((4'-chloro-1,1-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((1-meth-
ylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-cyano-4--
((3-(dimethylamino)propyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((3-pyrrolidin-1-4-(4-((4'-chloro-1,1-biphenyl-2-yl)methyl)piperazin-1-yl)-
-N-((4-((3-(dimethylamino)propyl)amino)-3-(trifluoromethyl)phenyl)sulfonyl-
)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(iso-
propyl(methyl)amino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzami-
de;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(3-(d-
imethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-
-3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-(4-methylpiperazin-1-yl)propyl)amino-
)-3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)-
phenyl)sulfonyl)benzamide
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrop-
henyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-(4-methylpiperazin-1-yl)propyl)amino-
)-3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-(3-(dimethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-(1H-indo-
l-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-
-3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)-
phenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrop-
henyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)--
3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino-3-
-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-(3-(dimethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-(1H-indo-
l-4-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-(4-methylpiperazin-1-yl)-3-nitrophenyl)s-
ulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yl
oxy)-N-((3-nitro-4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)phenyl)-
sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-(((4-(dimethylamino)-1-methylpiperidin-4-yl)methyl)amino)-3-n-
itrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydro-
-1,4-benzodioxin-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)a-
mino)phenyl)sulfonyl)benzamide;
5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-1,1'-biphenyl-2-ca-
rboxamide;
5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((-
4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-1,1'-biphenyl-2-
-carboxamide;
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)-
sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-4-(3-piperidin-1-ylpropoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)-
sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)s-
ulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-4-(3-(dimethylamino)propoxy)-1,1'-biphenyl-2-yl)methyl)p-
iperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl-
)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((t-
rifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(3-(dimethylamino)propoxy)-1,1'-biphenyl-2-yl)methyl)p-
iperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-(-
(trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(3-(dimethylamino)propoxy)-1,1'-biphenyl-2-yl)methyl)p-
iperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-(-
(trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((-
trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-(dimethyl
amino)ethoxy)-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((3-
-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)-
sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfony-
l)-2-phenoxybenzamide;
4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((-
trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-y-
lmethyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-(dimethyl
amino)ethoxy)-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-ylo-
xy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)b-
enzamide;
4-(4-((4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)m-
ethyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-p-
yran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-y-
lmethyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-y-
lmethyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl-
methyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-3-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-ylmethyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-3-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl-
methyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl-
)-2-phenoxybenzamide;
4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl-
)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl-
)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)-
amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-N-((3-nitro-4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino-
)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-4-(2-pyrrolidin-1-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)-
sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-4-(2-(diisopropylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl-
)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phen-
yl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydro-
-1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)ph-
enyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-
-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfo-
nyl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclooct-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H--
indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfon-
yl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-
-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfo-
nyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en-1-yl)methyl)piperazi-
n-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitro-
phenyl)sulfonyl)benzamide;
4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)p-
iperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)--
3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclooct-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H--
indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfony-
l)benzamide;
4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-
-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfon-
yl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-
-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfon-
yl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H--
indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfony-
l)benzamide;
4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)p-
iperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)--
3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-
-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfon-
yl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-phe-
noxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(dim-
ethylamino)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morp-
holin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(dim-
ethylamino)butyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((1-(phenylsulfonyl)piperidin-4-yl)amino)phenyl)sulfonyl)-2-phenoxybenzami-
de;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-
-4-((1-(quinolin-8-ylsulfonyl)piperidin-4-yl)amino)phenyl)sulfonyl)-2-phen-
oxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((-
4-((1-(phenylsulfonyl)piperidin-4-yl)amino)-3-((trifluoromethyl)sulfonyl)p-
henyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((-
4-((1-(quinolin-8-ylsulfonyl)piperidin-4-yl)amino)-3-((trifluoromethyl)sul-
fonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(((1S)-3--
(dimethylamino)-1-thien-2-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-phenox-
ybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((thien-2-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((-
4-((tetrahydro-2-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phen-
yl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((2-(1H-1,2,3-triazol-1-yl)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide-
;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-
-((2-(2H-1,2,3-triazol-2-yl)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamid-
e; 4-(4-((4'-chloro
1,1-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)-
amino)-3-nitrophenyl)sulfonyl)-2-(2-naphthyloxy)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((2-(2-oxopyridin-1(2H)-yl)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide-
;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-
-((2-(pyridin-2-yloxy)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((2-pyridin-4-ylethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-((trifluoromethyl)sulfonyl-
)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-(trifluoromethyl)phenyl)su-
lfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((3-cyano-4-((3-(dimethylamino)propyl)amino)phenyl)sulfonyl)-2-(1-
H-indol-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((1-tetrahydro-2H-pyran-4-ylpipe-
ridin-4-yl)amino)phenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-(4-methylpiperazin-1-yl)amino)-3-nitroph-
enyl)sulfonyl)benzamide;
4-(4-(1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl)piperazin-1-yl)-2-(1H-indol-4-
-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfon-
yl)benzamide;
N-((4-(((4-aminotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulf-
onyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)pipe-
razin-1-yl)-2-(H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl-
)amino]phenyl}sulfonyl)benzamide;
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino-
]-3-nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sul-
fonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylm-
ethyl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylm-
ethyl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4--
ylmethyl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-
-3-nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-
-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;
N-[(4-{[(3S,4R)-1-benzyl-3-hydroxypiperidin-4-yl]amino}-3-nitrophenyl)sul-
fonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino-
}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrop-
henyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino-
}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulf-
onyl]-2-(1H-indol-4-yloxy)benzamide;
4-[4-({4'-chloro-3-[3-(dimethylamino)propyl]-1,1'-biphenyl-2-yl}methyl)pi-
perazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-y-
lmethyl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulf-
onyl]-2-(1H-indol-5-yloxy)benzamide;
4-{4-[(4'-chloro-4-morpholin-4-yl-1,1'-biphenyl-2-yl)methyl]piperazin-1-y-
l}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)ami-
no]phenyl}sulfonyl)benzamide;
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pi-
perazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-
-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]--
2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-ni-
trophenyl}sulfonyl)benzamide;
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pi-
perazin-1-yl]-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide;
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-
-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benza-
mide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-{[4-({[4-(dimethylamino)tetrahydro-2H-pyran-4-yl]methyl}amin-
o)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;
N-({4-[(2-aminocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlo-
rophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indo-
l-5-yloxy)benzamide;
4-[4-({4'-chloro-4-[3-(dimethylamino)prop-1-ynyl]-1,1'-biphenyl-2-yl}meth-
yl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyra-
n-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperi-
din-4-yl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[2-(4-hydroxy-1-methylpiperidin-4-yl)ethyl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-yl)piperidin--
4-yl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[4'-chloro-4-(2-hydroxyethoxy)-1,1'-biphenyl-2-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)-
amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)su-
lfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trif-
luoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperi-
din-4-yl]amino}phenyl)sulfonyl]benzamide;
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-
-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benza-
mide;
4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(-
hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperid-
in-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;
4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydro-
xymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-
-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trif-
luoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[4'-chloro-4-(2-hydroxyethoxy)-1,1'-biphenyl-2-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]-
amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]-
amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1--
yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophen-
yl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1--
yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperid-
in-4-yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1--
yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophen-
yl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitrop-
henyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitrop-
henyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-morpholin-4-ylcyclohexyl)methyl]ami-
no}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-ylmethyl)pipe-
ridin-4-yl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-4-ylmethyl)pipe-
ridin-4-yl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3--
nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(2-hydroxyethyl)piperazin-1-yl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3--
nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(3-fluoropropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-indol-5-yloxy)benzamide;
4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydro-
xymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2-
H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(-
hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(1-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]--
2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}su-
lfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2-hydroxy-1-tetrahydro-2H-pyran-4-ylethyl)amino]-3-nitrophe-
nyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-({1-[2-(1H-pyrazol-1-yl)ethyl]pi-
peridin-4-yl}amino)phenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl-
)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfonyl}ben-
zamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfo-
nyl}benzamide;
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-
-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benza-
mide;
4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmeth-
yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-5-morpholin-4-ylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylme-
thyl)amino]phenyl}sulfonyl)benzamide;
N-[(4-{[(1-aminocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-
-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2--
(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxopyrrolidin-1-yl)ethyl]-
amino}phenyl)sulfonyl]benzamide;
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-5-
-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfon-
yl)benzamide;
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazi-
n-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethy-
l)amino]phenyl}sulfonyl)benzamide;
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazi-
n-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitro-
phenyl}sulfonyl)benzamide;
4-{4-[(1R)-1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-in-
dol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)benzamide;
4-{4-[(1S)-1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-in-
dol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)benzamide;
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazi-
n-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitro-
phenyl}sulfonyl)benzamide;
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazi-
n-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpip-
eridin-4-yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-
-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulf-
onyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-3-ylmethyl-
)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulf-
onyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)p-
henyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3-methyloxetan-3-yl)methyl]amino}-3-n-
itrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methoxycyclohexyl)amino]-3-nitrophen-
yl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[3-(1,1-dioxidothiomorpholin-4-yl)propyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxopiperidin-1-yl)ethyl]am-
ino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxoimidazolidin-1-yl)ethy-
l]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-pyridin-4-ylethyl)amino]phen-
yl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-morpholin-4-yl-3-nitrophenyl)sulfonyl]be-
nzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}p-
iperazin-1-yl)-2-(l
1H-indol-5-yloxy)-N-{[4-(4-methoxypiperidin-1-yl)-3-nitrophenyl]sulfonyl}-
benzamide;
4-(4-{[2-(4-chlorophenyl)-5-pyrrolidin-1-ylcyclohex-1-en-1-yl]m-
ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-p-
yran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]a-
mino}phenyl)sulfonyl]benzamide;
4-[4-({4'-chloro-4-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pi-
perazin-1-yl]-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-4-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-3-nitrophenyl}sulfon-
yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]--
3-(trifluoromethyl)phenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({(4-[2-(1,3-dioxolan-2-yl)ethyl]-3-nitrophenyl}sulfonyl)-2-(1H-i-
ndol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy-
)phenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]a-
mino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methyl-5-oxopyrrolidin-3-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(l
1H-indol-5-yloxy)-N-({4-[(1-methyl-6-oxopiperidin-3-yl)amino]-3-nitrophen-
yl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulf-
onyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulf-
onyl}benzamide;
4-(4-{[4-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl]methyl}piperazin-1-yl)-
-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino-
]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methyloxetan-3-yl)methoxy]-3-nitroph-
enyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1-oxidotetrahydro-2H-thiopyra-
n-4-yl)methyl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1,3-thiazol-5-ylmethyl)amino]p-
henyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy-
)phenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl-
)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-tetrahydro-2H-pyran-4-ylethy-
l)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amin-
o}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitr-
ophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[3-(methylsulfonyl)propyl]amino}-3-nitr-
ophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[3-(1,1-dioxidothiomorpholin-4-yl)propyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethyl-
)phenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indol--
5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitr-
ophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-3-nitrophenyl}sulfon-
yl)-2-(1H-indol-4-yloxy)benzamide; 4-(4-{[2-(4
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
-indol-5-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amino}phenyl)sul-
fonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}-3-ni-
trophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2,2-difluoroethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indo-
l-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]--
3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]--
3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4,4-difluorocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-
-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sul-
fonyl)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[4-(4-chlorophenyl)-1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl]methy-
l}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]-
carbonyl}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromet-
hyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]--
2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-n-
itrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]--
2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-n-
itrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethox-
y)phenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromet-
hyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[3-(methylsulfonyl)propoxy]-3-nitropheny-
l}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}s-
ulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}s-
ulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-y-
loxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-y-
loxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[(3R)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sul-
fonyl}-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[Cis-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulf-
onyl}-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]ph-
enyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]ph-
enyl}sulfonyl)benzamide;
N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfony-
l)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl-N-[(4-{[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}-3-nitrophenyl-
)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sul-
fonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-(methylamino)-3-[(trifluoromethyl)sulfon-
yl]phenyl}sulfonyl)benzamide;
N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(-
4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-y-
l)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[4-(4-chlorophenyl)-6-isopropoxypyridin-3-yl]methyl}piperazin-1-yl)-
-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino-
]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(1,3-
-thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(2-methoxyethyl)amino]carbonyl}phenyl)-
sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfony-
l}-2-(1H-indol-5-yloxy)benzamide;
N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-
-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino-
}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H--
indol-5-yloxy)benzamide;
N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-
-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino-
}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[4'-chloro-5-(trifluoromethyl)-1,1'-biphenyl-2-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)-
amino]phenyl}sulfonyl)benzamide;
4-(4-{[4'-chloro-5-(trifluoromethyl)-1,1'-biphenyl-2-yl]methyl}-piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy-
)phenyl]sulfonyl}benzamide;
4-{4-[(5-tert-butyl-4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-
-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]p-
henyl}sulfonyl)benzamide;
4-{4-[(5-tert-butyl-4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-
-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-
sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phe-
nyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phe-
nyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]-
carbonyl}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-i-
ndol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-i-
ndol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trif-
luoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trif-
luoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfony-
l)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-[(trifl-
uoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}s-
ulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)oxy]-3-nitrophe-
nyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitr-
ophenyl}sulfonyl)benzamide;
4-(4-{[4-(4-chlorophenyl)-1-(3-hydroxypropyl)-1,2,5,6-tetrahydropyridin-3-
-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-
-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; benzyl
4-({[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl-
}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenyl-
]amino}methyl)piperidine-1-carboxylate;
N-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-
-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[4'-chloro-5-(trifluoromethyl)-1,1'-biphenyl-2-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiper-
idin-4-yl)amino]phenyl}sulfonyl)benzamide;
4-{4-[(5-tert-butyl-4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-
-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4--
yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-methyl-1H-imidazol-5-yl)methyl]amin-
o}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylsulfonyl)phenyl]sulfonyl}-
benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl-
}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitropheny-
l}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nit-
rophenyl}sulfonyl)benzamide;
N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(-
4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-y-
l)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-{[6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]--
5-(1,3-thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(3,3-dimethylbutyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indo-
l-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(1S)-1-(hydroxymethyl)-3-methylbutyl]amino}-3-nitrophenyl)s-
ulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(2R)-tetrahydrofuran-2-ylmethy-
l]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(1R)-1-(hydroxymethyl)-2-methylpropyl]amino}-3-nitrophenyl)-
sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methoxyphenyl)amino]-3-nitrophenyl}s-
ulfonyl)benzamide;
N-[(4-{[2-(1,3-benzodioxol-5-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-
-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl-
)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(2-oxopyrrolidin-1-yl)propyl-
]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-hydroxyphenyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol--
5-yloxy)benzamide;
N-{[4-({2-[4-(aminosulfonyl)phenyl]ethyl}amino)-3-nitrophenyl]sulfonyl}-4-
-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
-yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[3-(1H-imidazol-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1S)-1-phenylethyl]amino}pheny-
l)sulfonyl]benzamide;
N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sul-
fonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitro-
phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitro-
phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylsulfonyl)phenyl]sulfonyl}benzamid-
e;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(methylsulfonyl)phenyl]sulfonyl}benzam-
ide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitroph-
enyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3--
yl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfony-
l}-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfon-
yl}-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-cyano-6-(morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-in-
dol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpipe-
ridin-4-yl)oxy]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitr-
ophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfo-
nyl}-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H--
indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3--
yl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(3-hydroxy-4-methoxyphenyl)amino]-3-nitrophenyl}sulfonyl)-2--
(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2,3-dihydro-1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)ami-
no]-3-nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(py-
ridin-3-ylamino)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phen-
yl}sulfonyl)-2-(pyridin-3-ylamino)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phen-
yl}sulfonyl)-2-(pyridin-3-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1,2,3,4-tetrahydroisoquinolin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indazol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmeth-
yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indazol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpi-
peridin-4-yl)amino]phenyl}sulfonyl)benzamide;
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-indazol-4-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)ami-
no]-3-nitrophenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-y-
lmethyl)amino]phenyl}sulfonyl)benzamide;
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}su-
lfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}su-
lfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3--
yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrro-
lidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-y-
l)methoxy]-3-nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluorometh-
yl)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)su-
lfonyl]-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfony-
l]-2-(1H-indazol-4-yloxy)benzamide;
N-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3-
-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
Trans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-
-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin-
-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-
-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-
-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide;
N-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-
-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-chloro-6-(tetrahydrofuran-3-ylmethoxy)pyridin-3-yl]sulfonyl}--
2-(1H-indazol-4-yloxy)benzamide;
Trans-N-({5-chloro-6-[(4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-
-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3--
yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-(indazol-4-yloxy)benzamide;
2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)m-
orpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-
-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)m-
orpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-
-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridi-
n-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]-
methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridi-
n-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]-
methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfon-
yl}-2-(1H-indazol-4-yloxy)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin--
3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethy-
l]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrr-
olidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]-
methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)me-
thyl]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-oxetan-3-ylmorpholin-
-2-yl)methyl]amino}phenyl)sulfonyl]benzamide;
N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}o-
xy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-
-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amin-
o)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-(1H-indazol-4-yloxy)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)mor-
pholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)mor-
pholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmet-
hyl)amino]phenyl}sulfonyl)benzamide;
Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)meth-
yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4--
yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H--
pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran--
4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}m-
ethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridi-
n-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]-
methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-indazol-4-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]am-
ino}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indazo-
l-4-yloxy)benzamide;
N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-
-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)-
amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3--
nitrophenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)ami-
no]-3-nitrophenyl}sulfonyl)benzamide;
Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexy-
l)amino]-3-nitrophenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]-
amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({(2R)-4-[2-(2-methoxyethoxy)eth-
yl]morpholin-2-yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]-
amino}-3-nitrophenyl)sulfonyl]benzamide;
N-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(-
1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1--
en-1-yl]methyl}piperazin-1-yl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2--
yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[6-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}m-
ethoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)be-
nzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}p-
iperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl-
}sulfonyl)-2-phenoxybenzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-chloro-6-(2-tetrahydrofuran-2-ylethoxy)pyridin-3-yl]sulfonyl}-
-2-(1H-indazol-4-yloxy)benzamide;
Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyanocyclohexyl)methyl-
]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4,4-difluorocyclohexyl)metho-
xy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-
-en-1-yl]methyl}piperazin-1-yl)benzamide;
N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl-
)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}su-
lfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]m-
ethyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-cyano-6-(2-tetrahydro-2H-pyran-4-ylethoxy)pyridin-3-yl]sulfon-
yl}-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oc-
t-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-p-
henoxy-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.-
1]hept-3-yl]amino}piperidin-1-yl)benzamide;
N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxy-4-
-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-
-yl]amino}piperidin-1-yl)benzamide;
N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-p-
henoxy-4-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]h-
ept-3-yl]amino}piperidin-1-yl)benzamide;
N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxy-4-
-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl-
]amino}piperidin-1-yl)benzamide;
4-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)piper-
azin-1-yl]-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-
-phenoxybenzamide;
4-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)piper-
azin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sul-
fonyl)-2-phenoxybenzamide;
4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-N-({3-nitro-4-
-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamid-
e;
4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-2-phenoxy-N-
-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]-
phenyl}sulfonyl)benzamide;
4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-2-phenoxy-N-(-
{4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-N-({4-[(3-mor-
pholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide;
4-(4-{2-[(4R,7S)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoinden-5-yl]benzyl}-
piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pheny-
l}sulfonyl)-2-phenoxybenzamide;
4-[4-(2-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzyl)p-
iperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl-
}sulfonyl)-2-phenoxybenzamide;
4-[4-(2-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzylid-
ene)piperidin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]p-
henyl}sulfonyl)-2-phenoxybenzamide;
4-[4-(3-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzyl)p-
iperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl-
}sulfonyl)-2-phenoxybenzamide; and therapeutically acceptable
salts, prodrugs, salts of prodrugs and metabolites thereof.
Another embodiment pertains to a composition for treating bladder
cancer, brain cancer, breast cancer, bone marrow cancer, cervical
cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal
cancer, hepatocellular cancer, lymphoblastic leukemia, follicular
lymphoma, lymphoid malignancies of T-cell or B-cell origin,
melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian
cancer, non-small cell lung cancer, chronic lymphocytic leukemia,
myeloma, prostate cancer, small cell lung cancer or spleen cancer,
said composition comprising an excipient and a therapeutically
effective amount of the compound of Formula (I).
Another embodiment pertains to a method of treating bladder cancer,
brain cancer, breast cancer, bone marrow cancer, cervical cancer,
chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,
hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,
lymphoid malignancies of T-cell or B-cell origin, melanoma,
myelogenous leukemia, myeloma, oral cancer, ovarian cancer,
non-small cell lung cancer, chronic lymphocytic leukemia, myeloma,
prostate cancer, small cell lung cancer or spleen cancer in a
patient, said method comprising administering to the patient a
therapeutically effective amount of Formula (I).
Another embodiment pertains to a method of treating bladder cancer,
brain cancer, breast cancer, bone marrow cancer, cervical cancer,
chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,
hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,
lymphoid malignancies of T-cell or B-cell origin, melanoma,
myelogenous leukemia, myeloma, oral cancer, ovarian cancer,
non-small cell lung cancer, chronic lymphocytic leukemia, myeloma,
prostate cancer, small cell lung cancer or spleen cancer in a
patient, said method comprising administering to the patient
therapeutically effective amount of the compound of Formula (I) and
a therapeutically effective amount of one additional therapeutic
agent or more than one additional therapeutic agent.
DETAILED DESCRIPTION OF THE INVENTION
Variable moieties herein are represented by identifiers (capital
letters with numerical and/or alphabetical superscripts) and may be
specifically embodied.
It is meant to be understood that proper valences are maintained
for all moieties and combinations thereof, that monovalent moieties
having more than one atom are drawn from left to right and are
attached through their left ends, and that divalent moieties are
also drawn from left to right.
It is also meant to be understood that a specific embodiment of a
variable moiety herein may be the same or different as another
specific embodiment having the same identifier.
The term "alkenyl" as used herein, means a straight or branched
hydrocarbon chain containing from 2 to 10 carbons and containing at
least one carbon-carbon double bond. The term "C.sub.x-C.sub.y
alkyl" means a straight or branched hydrocarbon chain containing at
least one carbon-carbon double bond containing x to y carbon atoms.
The term "C.sub.3-C.sub.6 alkenyl" means an alkenyl group
containing 3-6 carbon atoms. Representative examples of alkenyl
include, but are not limited to, buta-2,3-dienyl, ethenyl,
2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl,
2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.
The term "alkenylene" means a divalent group derived from a
straight or branched chain hydrocarbon of 2 to 4 carbon atoms and
contains at least one carbon-carbon double bond. The term
"C.sub.x-C.sub.y alkylene" means a divalent group derived from a
straight or branched hydrocarbon chain containing at least one
carbon-carbon double bond and containing x to y carbon atoms.
Representative examples of alkenylene include, but are not limited
to, --CH.dbd.CH-- and --CH.sub.2CH.dbd.CH--.
The term "alkyl" as used herein, means a straight or branched,
saturated hydrocarbon chain containing from 1 to 10 carbon atoms.
The term "C.sub.x-C.sub.y alkyl" means a straight or branched
chain, saturated hydrocarbon containing x to y carbon atoms. For
example "C.sub.1-C.sub.6 alkyl" means a straight or branched chain,
saturated hydrocarbon containing 2 to 6 carbon atoms.
Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,
2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,
and n-decyl.
The term "alkylene" means a divalent group derived from a straight
or branched, saturated hydrocarbon chain of 1 to 10 carbon atoms,
for example, of 1 to 4 carbon atoms. The term "C.sub.x-C.sub.y
alkylene" means a divalent group derived from a straight or
branched chain, saturated hydrocarbon containing x to y carbon
atoms. For example "C.sub.2-C.sub.6 alkylene" means a straight or
branched chain, saturated hydrocarbon containing 2 to 6 carbon
atoms. Representative examples of alkylene include, but are not
limited to, --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
and --CH.sub.2CH(CH.sub.3)CH.sub.2--.
The term "alkynyl" as used herein, means a straight or branched
chain hydrocarbon group containing from 2 to 10 carbon atoms and
containing at least one carbon-carbon triple bond. The term
"C.sub.x-C.sub.y alkynyl" means a straight or branched chain
hydrocarbon group containing from x to y carbon atoms. For example
"C.sub.3-C.sub.6 alkynyl" means a straight or branched chain
hydrocarbon group containing from 3 to 6 carbon atoms and
containing at least one carbon-carbon triple bond. Representative
examples of alkynyl include, but are not limited to, acetylenyl,
1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
The term "alkynylene," as used herein, means a divalent radical
derived from a straight or branched chain hydrocarbon group
containing from 2 to 10 carbon atoms and containing at least one
carbon-carbon triple bond.
The term "aryl" as used herein, means phenyl.
The term "cyclic moiety," as used herein, means benzene, phenyl,
phenylene, cycloalkane, cycloalkyl, cycloalkylene, cycloalkene,
cycloalkenyl, cycloalkenylene, cycloalkyne, cycloalkynyl,
cycloalkynylene, heteroarene, heteroaryl, heterocycloalkane,
heterocycloalkyl, heterocycloalkene, heterocycloalkenyl and
spiroalkyl.
The term "cycloalkylene" or cycloalkyl" or "cycloalkane" as used
herein, means a monocyclic or bridged hydrocarbon ring system. The
monocyclic cycloalkyl is a carbocyclic ring system containing three
to ten carbon atoms, zero heteroatoms and zero double bonds.
Examples of monocyclic ring systems include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The monocyclic ring may contain one or two alkylene bridges, each
consisting of one, two, or three carbon atoms, each linking two
non-adjacent carbon atoms of the ring system. Representative
examples of such bridged cycloalkyl ring systems include, but are
not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,
bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, bicyclo[3.2.2]nonane,
bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane,
tricyclo[3.3.1.0.sup.3,7]nonane (octahydro-2,5-methanopentalene or
noradamantane), and tricyclo[3.3.1.1.sup.3,7]decane (adamantane).
The monocyclic and bridged cycloalkyl can be attached to the parent
molecular moiety through any substitutable atom contained within
the ring system.
The term "cycloalkenylene," or "cycloalkenyl" or "cycloalkene" as
used herein, means a monocyclic or a bridged hydrocarbon ring
system. The monocyclic cycloalkenyl has four to ten carbon atoms
and zero heteroatoms. The four-membered ring systems have one
double bond, the five- or six-membered ring systems have one or two
double bonds, the seven- or eight-membered ring systems have one,
two, or three double bonds, and the nine- or ten-membered rings
have one, two, three, or four double bonds. Representative examples
of monocyclic cycloalkenyl groups include, but are not limited to,
cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and
cyclooctenyl. The monocyclic cycloalkenyl ring may contain one or
two alkylene bridges, each consisting of one, two, or three carbon
atoms, each linking two non-adjacent carbon atoms of the ring
system. Representative examples of the bridged cycloalkenyl groups
include, but are not limited to, bicyclo[2.2.1]hept-2-ene,
4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl, and
1,6-dihydro-pentalene. The monocyclic and bridged cycloalkenyl can
be attached to the parent molecular moiety through any
substitutable atom contained within the ring systems.
The term "cycloalkyne," or "cycloalkynyl," or "cycloalkynylene," as
used herein, means a monocyclic or a bridged hydrocarbon ring
system. The monocyclic cycloalkynyl has eight or more carbon atoms,
zero heteroatoms, and one or more triple bonds. The monocyclic
cycloalkynyl ring may contain one or two alkylene bridges, each
consisting of one, two, or three carbon atoms, each linking two
non-adjacent carbon atoms of the ring system. The monocyclic and
bridged cycloalkynyl can be attached to the parent molecular moiety
through any substitutable atom contained within the ring
systems.
The term "heteroarene," or "heteroaryl," or "heteroarylene," as
used herein, means a five-membered or six-membered aromatic ring
having at least one carbon atom and one or more than one
independently selected nitrogen, oxygen or sulfur atom. The
heteroarenes of this invention are connected through any adjacent
atoms in the ring, provided that proper valences are maintained.
Representative examples of heteroaryl include, but are not limited
to, furanyl (including, but not limited thereto, furan-2-yl),
imidazolyl (including, but not limited thereto, 1H-imidazol-1-yl),
isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl
(e.g. pyridin-4-yl, pyridin-2-yl, pyridin-3-yl), pyridazinyl,
pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl,
thiadiazolyl, 1,3-thiazolyl, thienyl (including, but not limited
thereto, thien-2-yl, thien-3-yl), triazolyl, and triazinyl.
The term "heterocycloalkane," or "heterocycloalkyl," or
"heterocycloalkylene," as used herein, means monocyclic or bridged
three-, four-, five-, six-, seven-, or eight-membered ring
containing at least one heteroatom independently selected from the
group consisting of O, N, and S and zero double bonds. The
monocyclic and bridged heterocycloalkane are connected to the
parent molecular moiety through any substitutable carbon atom or
any substitutable nitrogen atom contained within the rings. The
nitrogen and sulfur heteroatoms in the heterocycle rings may
optionally be oxidized and the nitrogen atoms may optionally be
quarternized. Representative examples of heterocycloalkane groups
include, but are not limited to, 8-azabicyclo[3.2.1]octane,
3-azabicyclo[3.2.2]nonane, morpholinyl, tetrahydropyranyl,
pyrrolidinyl, piperidinyl, dioxolanyl, tetrahydrofuranyl,
thiomorpholinyl, 1,4-dioxanyl, tetrahydrothienyl,
tetrahydrothiopyranyl, oxetanyl, piperazinyl, imidazolidinyl,
azetidine, azepanyl, aziridinyl, diazepanyl, dithiolanyl,
dithianyl, isoxazolidinyl, isothiazolidinyl, oxadiazolidinyl,
oxazolidinyl, pyrazolidinyl, tetrahydrothienyl, thiadiazolidinyl,
thiazolidinyl, thiomorpholinyl, trithianyl, and trithianyl.
The term "heterocycloalkene," or "heterocycloalkenyl," or
"heterocycloalkenylene," as used herein, means monocyclic or
bridged three-, four-, five-, six-, seven-, or eight-membered ring
containing at least one heteroatom independently selected from the
group consisting of O, N, and S and one or more double bonds. The
monocyclic and bridged heterocycloalkene are connected to the
parent molecular moiety through any substitutable carbon atom or
any substitutable nitrogen atom contained within the rings. The
nitrogen and sulfur heteroatoms in the heterocycle rings may
optionally be oxidized and the nitrogen atoms may optionally be
quarternized. Representative examples of heterocycloalkene groups
include, but are not limited to, 1,4,5,6-tetrahydropyridazinyl,
1,2,3,6-tetrahydropyridinyl, dihydropyranyl, imidazolinyl,
isothiazolinyl, oxadiazolinyl, isoxazolinyl, oxazolinyl, pyranyl,
pyrazolinyl, pyrrolinyl, thiadiazolinyl, thiazolinyl, and
thiopyranyl.
The term "phenylene," as used herein, means a divalent radical
formed by removal of a hydrogen atom from phenyl.
The term "spiroalkyl," as used herein, means alkylene, both ends of
which are attached to the same carbon atom and is exemplified by
C.sub.2-spiroalkyl, C.sub.3-spiroalkyl, C.sub.4-spiroalkyl,
C.sub.5-spiroalkyl, C.sub.6-spiroalkyl, C.sub.7-spiroalkyl,
C.sub.8-spiroalkyl, C.sub.9-spiroalkyl and the like.
The term "spiroheteroalkyl," as used herein, means spiroalkyl
having one or two CH.sub.2 moieties replaced with independently
selected O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and
one or two CH moieties unreplaced or replaced with N.
The term "spiroheteroalkenyl," as used herein, means spiroalkenyl
having one or two CH.sub.2 moieties replaced with independently
selected O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and
one or two CH moieties unreplaced or replaced with N and also means
spiroalkenyl having one or two CH.sub.2 moieties unreplaced or
replaced with independently selected O, C(O), CNOH, CNOCH.sub.3, S,
S(O), SO.sub.2 or NH and one or two CH moieties replaced with
N.
The term, "spirocyclo," as used herein, means two substituents on
the same carbon atom, that, together with the carbon atom to which
they are attached, form a cycloalkane, heterocycloalkane,
cycloalkene, or heterocycloalkene ring.
The term "C.sub.2-C.sub.5-spiroalkyl," as used herein, means
C.sub.2-spiroalkyl, C.sub.3-spiroalkyl, C.sub.4-spiroalkyl, and
C.sub.5-spiroalkyl.
The term "C.sub.2-spiroalkyl," as used herein, means eth-1,2-ylene,
both ends of which replace hydrogen atoms of the same CH.sub.2
moiety.
The term "C.sub.3-spiroalkyl," as used herein, means
prop-1,3-ylene, both ends of which replace hydrogen atoms of the
same CH.sub.2 moiety.
The term "C.sub.4-spiroalkyl," as used herein, means but-1,4-ylene,
both ends of which replace hydrogen atoms of the same CH.sub.2
moiety.
The term "C.sub.5-spiroalkyl," as used herein, means
pent-1,5-ylene, both ends of which replace hydrogen atoms of the
same CH.sub.2 moiety.
The term "C.sub.6-spiroalkyl," as used herein, means hex-1,6-ylene,
both ends of which replace hydrogen atoms of the same CH.sub.2
moiety.
The term "NH protecting group," as used herein, means
trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl,
para-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl,
chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl,
phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl,
tert-butoxycarbonyl, para-methoxybenzyloxycarbonyl,
3,4-dimethoxybenzyl-oxycarbonyl, 4-(phenylazo)benzyloxycarbonyl,
2-furfuryl-oxycarbonyl, diphenylmethoxycarbonyl,
1,1-dimethylpropoxy-carbonyl, isopropoxycarbonyl, phthaloyl,
succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl,
8-quinolyloxycarbonyl, benzyl, diphenylmethyl, triphenylmethyl,
2-nitrophenylthio, methanesulfonyl, para-toluenesulfonyl,
N,N-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene,
2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthyl-methylene,
3-hydroxy-4-pyridylmethylene, cyclohexylidene,
2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene,
2-acetylcyclohexylidene, 3,3-dimethyl-5-oxycyclo-hexylidene,
diphenylphosphoryl, dibenzylphosphoryl,
5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl, trimethylsilyl,
triethylsilyl, and triphenylsilyl.
The term "C(O)OH protecting group," as used herein, means methyl,
ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl,
tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl,
triphenylmethyl, para-nitrobenzyl, para-methoxybenzyl,
bis(para-methoxyphenyl)methyl, acetylmethyl, benzoylmethyl,
para-nitrobenzoylmethyl, para-bromobenzoylmethyl,
para-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl
2-tetrahydrofuranyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,
acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl,
phthalimidomethyl, succinimidomethyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl,
2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, methylthiomethyl,
2-methylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl,
3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl,
triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl,
tert-butyldiphenylsilyl, diphenylmethylsilyl, and
tert-butylmethoxyphenylsilyl.
The term "OH or SH protecting group," as used herein, means
benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl,
tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl,
isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl,
2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl,
2-(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl,
1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl,
S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl,
8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl,
dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl,
phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl,
1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl
(phenylmethyl), para-methoxybenzyl, 3,4-dimethoxybenzyl,
diphenylmethyl, triphenylmethyl, tetrahydrofuryl,
tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl,
methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl,
2,2,2-trichloro-ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl,
1-ethoxyethyl, methanesulfonyl, para-toluenesulfonyl,
trimethylsilyl, triethylsilyl, triisopropylsilyl,
diethylisopropylsilyl, tert-butyldimethylsilyl,
tert-butyldiphenylsilyl, diphenylmethylsilyl, and
tert-butylmethoxyphenylsilyl.
Compounds
Geometric isomers may exist in the present compounds. Compounds of
this invention may contain carbon-carbon double bonds or
carbon-nitrogen double bonds in the E or Z configuration, wherein
the term "E" represents higher order substituents on opposite sides
of the carbon-carbon or carbon-nitrogen double bond and the term
"Z" represents higher order substituents on the same side of the
carbon-carbon or carbon-nitrogen double bond as determined by the
Cahn-Ingold-Prelog Priority Rules. The compounds of this invention
may also exist as a mixture of "E" and "Z" isomers. Substituents
around a cycloalkyl or heterocycloalkyl are designated as being of
cis or trans configuration. Furthermore, the invention contemplates
the various isomers and mixtures thereof resulting from the
disposal of substituents around an adamantane ring system. Two
substituents around a single ring within an adamantane ring system
are designated as being of Z or E relative configuration. For
examples, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le
Noble J. Org. Chem. 1998, 63, 2758-2760 and E. L. Eliel, and S. H.
Wilen. (1994) Stereochemistry of Organic Compounds. New York, N.Y.:
John Wiley & Sons, Inc.
Compounds of this invention contain asymmetrically substituted
carbon atoms in the R or S configuration, in which the terms "R"
and "S" are as defined by the IUPAC 1974 Recommendations for
Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45,
13-10. Compounds having asymmetrically substituted carbon atoms
with equal amounts of R and S configurations are racemic at those
carbon atoms. Atoms with an excess of one configuration over the
other are assigned the configuration present in the higher amount,
preferably an excess of about 85%-90%, more preferably an excess of
about 95%-99%, and still more preferably an excess greater than
about 99%. Accordingly, this invention includes racemic mixtures,
relative and absolute stereoisomers, and mixtures of relative and
absolute stereoisomers.
Compounds of this invention containing NH, C(O)OH, OH or SH
moieties may have attached thereto prodrug-forming moieties. The
prodrug-forming moieties are removed by metabolic processes and
release the compounds having the freed hydroxyl, amino or
carboxylic acid in vivo. Prodrugs are useful for adjusting such
pharmacokinetic properties of the compounds as solubility and/or
hydrophobicity, absorption in the gastrointestinal tract,
bioavailability, tissue penetration, and rate of clearance.
Isotope Enriched or Labeled Compounds
Compounds of the invention can exist in isotope-labeled or
-enriched form containing one or more atoms having an atomic mass
or mass number different from the atomic mass or mass number most
abundantly found in nature. Isotopes can be radioactive or
non-radioactive isotopes. Isotopes of atoms such as hydrogen,
carbon, phosphorous, sulfur, fluorine, chlorine, and iodine
include, but are not limited to .sup.2H, .sup.3H, .sup.13C,
.sup.14C, .sup.15N, .sup.18O, .sup.32P, .sup.35S, .sup.18F,
.sup.36Cl, and .sup.125I. Compounds that contain other isotopes of
these and/or other atoms are within the scope of this
invention.
In another embodiment, the isotope-labeled compounds contain
deuterium (.sup.2H), tritium (.sup.3H) or .sup.14C isotopes.
Isotope-labeled compounds of this invention can be prepared by the
general methods well known to persons having ordinary skill in the
art. Such isotope-labeled compounds can be conveniently prepared by
carrying out the procedures disclosed in the Examples disclosed
herein and Schemes by substituting a readily available
isotope-labeled reagent for a non-labeled reagent. In some
instances, compounds may be treated with isotope-labeled reagents
to exchange a normal atom with its isotope, for example, hydrogen
for deuterium can be exchanged by the action of a deuteric acid
such as D.sub.2SO.sub.4/D.sub.2O. In addition to the above,
relevant procedures and intermediates are disclosed, for instance,
in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996); Brickner, S J
et al., J Med Chem, 39(3), 673 (1996); Mallesham, B et al., Org
Lett, 5(7), 963 (2003); PCT publications WO1997010223,
WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189;
7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013;
and US Patent Application Publication Nos. 20090137457;
20090131485; 20090131363; 20090118238; 20090111840; 20090105338;
20090105307; 20090105147; 20090093422; 20090088416; and
20090082471, the methods are hereby incorporated by reference.
The isotope-labeled compounds of the invention may be used as
standards to determine the effectiveness of Bcl-2 inhibitors in
binding assays. Isotope containing compounds have been used in
pharmaceutical research to investigate the in vivo metabolic fate
of the compounds by evaluation of the mechanism of action and
metabolic pathway of the nonisotope-labeled parent compound (Blake
et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic
studies are important in the design of safe, effective therapeutic
drugs, either because the in vivo active compound administered to
the patient or because the metabolites produced from the parent
compound prove to be toxic or carcinogenic (Foster et al., Advances
in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985;
Kato et al., J. Labelled Comp. Radiopharmaceut., 36(10):927-932
(1995); Kushner et al., Can. J. Physiol. Pharmacol., 77, 79-88
(1999).
In addition, non-radio active isotope containing drugs, such as
deuterated drugs called "heavy drugs," can be used for the
treatment of diseases and conditions related to Bcl-2 activity.
Increasing the amount of an isotope present in a compound above its
natural abundance is called enrichment. Examples of the amount of
enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79,
84, 88, 92, 96, to about 100 mol %. Replacement of up to about 15%
of normal atom with a heavy isotope has been effected and
maintained for a period of days to weeks in mammals, including
rodents and dogs, with minimal observed adverse effects (Czajka D M
and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F,
Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J.
Physiol. 1961 201: 357). Acute replacement of as high as 15%-23% in
human fluids with deuterium was found not to cause toxicity
(Blagojevic N et al. in "Dosimetry & Treatment Planning for
Neutron Capture Therapy", Zamenhof R, Solares G and Harling O Eds.
1994. Advanced Medical Publishing, Madison Wis. pp. 125-134;
Diabetes Metab. 23: 251 (1997)).
Stable isotope labeling of a drug can alter its physico-chemical
properties such as pKa and lipid solubility. These effects and
alterations can affect the pharmacodynamic response of the drug
molecule if the isotopic substitution affects a region involved in
a ligand-receptor interaction. While some of the physical
properties of a stable isotope-labeled molecule are different from
those of the unlabeled one, the chemical and biological properties
are the same, with one important exception: because of the
increased mass of the heavy isotope, any bond involving the heavy
isotope and another atom will be stronger than the same bond
between the light isotope and that atom. Accordingly, the
incorporation of an isotope at a site of metabolism or enzymatic
transformation will slow said reactions potentially altering the
pharmcokinetic profile or efficacy relative to the non-isotopic
compound.
Amides, Esters and Prodrugs
Prodrugs are derivatives of an active drug designed to ameliorate
some identified, undesirable physical or biological property. The
physical properties are usually solubility (too much or not enough
lipid or aqueous solubility) or stability related, while
problematic biological properties include too rapid metabolism or
poor bioavailability which itself may be related to a
physicochemical property.
Prodrugs are usually prepared by: a) formation of ester, hemi
esters, carbonate esters, nitrate esters, amides, hydroxamic acids,
carbamates, imines, Mannich bases, phosphates, phosphate esters,
and enamines of the active drug, b) functionalizing the drug with
azo, glycoside, peptide, and ether functional groups, c) use of
aminals, hemi-aminals, polymers, salts, complexes, phosphoramides,
acetals, hemiacetals, and ketal forms of the drug. For example, see
Andrejus Korolkovas's, "Essentials of Medicinal Chemistry", John
Wiley-Interscience Publications, John Wiley and Sons, New York
(1988), pp. 97-118, which is incorporated in its entirety by
reference herein
Esters can be prepared from substrates of formula (I) containing
either a hydroxyl group or a carboxy group by general methods known
to persons skilled in the art. The typical reactions of these
compounds are substitutions replacing one of the heteroatoms by
another atom, for example:
##STR00006##
Amides can be prepared from substrates of formula (I) containing
either an amino group or a carboxy group in similar fashion. Esters
can also react with amines or ammonia to form amides.
##STR00007##
Another way to make amides from compounds of formula (I) is to heat
carboxylic acids and amines together.
##STR00008##
In Schemes 2 and 3 above, R and R' are independently substrates of
formula (I), alkyl or hydrogen.
Suitable groups for A.sup.1, B.sup.1, D.sup.1, E.sup.1, Y.sup.1,
and Z.sup.1 in compounds of Formula (I) are independently selected.
The described embodiments of the present invention may be combined.
Such combination is contemplated and within the scope of the
present invention. For example, it is contemplated that embodiments
for any of A.sup.1, B.sup.1, D.sup.1, E.sup.1, Y.sup.1, and Z.sup.1
can be combined with embodiments defined for any other of A.sup.1,
B.sup.1, D.sup.1, E.sup.1, Y.sup.1, and Z.
One embodiment of this invention, therefore, pertains to compounds
or therapeutically acceptable salts, prodrugs or salts of prodrugs
thereof, which are useful as selective inhibitors one or more than
one anti-apoptotic protein family member, the compounds having
formula (I)
##STR00009## wherein A.sup.1 is N or C(A.sup.2);
one or two or three or each of A.sup.2, B.sup.1, D.sup.1 and
E.sup.1 are independently selected R.sup.1, OR.sup.1, SR.sup.1,
S(O)R.sup.1, SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1,
OC(O)R.sup.1, NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1,
C(O)N(R.sup.1).sub.2, NHC(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)NHR.sup.1, NR.sup.1C(O)N(R.sup.1).sub.2,
SO.sub.2NHR.sup.1, SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NHSO.sub.2NHR.sup.1 or N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, and
the remainder are independently selected H, F, Cl, Br, I, CN,
CF.sub.3, C(O)OH, C(O)NH.sub.2 or C(O)OR.sup.1A; and
Y.sup.1 is H, CN, NO.sub.2, C(O)OH, F, Cl, Br, I, CF.sub.3,
OCF.sub.3, CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, R.sup.17,
OR.sup.17, C(O)R.sup.17, C(O)OR.sup.17, SR.sup.17, NH.sub.2,
NHR.sup.17, N(R.sup.17).sub.2, NHC(O)R.sup.17, C(O)NH.sub.2,
C(O)NHR.sup.17, C(O)N(R.sup.17).sub.2, NHS(O)R.sup.7 or
NHSO.sub.2R.sup.17;
or
B.sup.1 and Y.sup.1, together with the atoms to which they are
attached, are imidazole or triazole; and
one or two or each of A.sup.2, D.sup.1 and E.sup.1 are
independently selected R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NHC(O)OR.sup.1, NHC(O)NHR.sup.1,
N(CH.sub.3)C(O)N(CH.sub.3)R.sup.1, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1 or
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, and the remainder are
independently selected H, F, Cl, Br, I, CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
R.sup.1 is R.sup.2, R.sup.3, R.sup.4 or R.sup.5;
R.sup.1A is C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl or
C.sub.3-C.sub.6-alkynyl;
R.sup.2 is phenyl which is unfused or fused with arene, heteroarene
or R.sup.2A; R.sup.2A is cycloalkane or heterocycloalkane;
R.sup.3 is heteroaryl which is unfused or fused with benzene,
heteroarene or R.sup.3A; R.sup.3A is cycloalkane or
heterocycloalkane;
R.sup.4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with arene,
heteroarene or R.sup.4A; R.sup.4A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.5 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.6, NC(R.sup.6A)(R.sup.6B) R.sup.7, OR.sup.7,
SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7, NHR.sup.7,
N(R.sup.7).sub.2, C(O)R.sup.7, C(O)NH.sub.2, C(O)NHR.sup.7,
NHC(O)R.sup.7, NHSO.sub.2R.sup.7, NHC(O)OR.sup.7, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2, NHC(O)NH.sub.2,
NHC(O)NHR.sup.7, NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NH.sub.2,
NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NHR.sup.1, OH, (O), C(O)OH,
(O), N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br
or I substituents;
R.sup.6 is C.sub.2-C.sub.5-spiroalkyl, each of which is
unsubstituted or substituted with OH, (O), N.sub.3, CN, CF.sub.3,
CF.sub.2CF.sub.3, F, Cl, Br, I, NH.sub.2, NH(CH.sub.3) or
N(CH.sub.3).sub.2;
R.sup.6A and R.sup.6B are independently selected alkyl or, together
with the N to which they are attached, R.sup.6C;
R.sup.6 is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl or
piperidin-1-yl, each having one CH.sub.2 moiety unreplaced or
replaced with O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or
NH;
R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
R.sup.8 is phenyl which is unfused or fused with arene, heteroarene
or R.sup.8A;
R.sup.8A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.9 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.9A; R.sup.9A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.10 is C.sub.3-C.sub.10-cycloalkyl or
C.sub.4-C.sub.10-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.10A; R.sup.10A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.11 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.1, OR.sup.12, NHR.sup.12, N(R.sup.12).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.12, C(O)N(R.sup.12).sub.2, OH, (O),
C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl,
Br or I substituents;
R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16;
R.sup.13 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.13A; R.sup.13A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.14 is heteroaryl, each of which is unfused or fused with
arene, heteroarene or R.sup.14A; R.sup.14A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.15 is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene, each of which is unfused or fused with arene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.16 is alkyl, alkenyl or alkynyl;
R.sup.17 is R.sup.18, R.sup.19, R.sup.20 or R.sup.21;
R.sup.18 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.18A; R.sup.18A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.19 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.19A; R.sup.19A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.20 is C.sub.3-C.sub.10-cycloalkyl or
C.sub.4-C.sub.10-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.20A; R.sup.20A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.21 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.22, OR.sup.11, NHR.sup.22, N(R.sup.22).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.22, C(O)N(R.sup.22).sub.2, OH, (O),
C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl,
Br or I substituents;
R.sup.22 is R.sup.23, R.sup.24 or R.sup.25;
R.sup.23 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.23A; R.sup.23A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.24 is heteroarene which is unfused or fused with arene,
heteroarene or R.sup.24A; R.sup.24A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.25 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.25A; R.sup.25A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
Z.sup.1 is R.sup.26 or R.sup.27, each of which is substituted with
R.sup.28, R.sup.29 or R.sup.30, each of which is substituted with
F, Cl, Br, I, CH.sub.2R.sup.37, CH(R.sup.31)(R.sup.37),
C(R.sup.31)(R.sup.31A)(R.sup.37), C(O)R.sup.37, OR.sup.37,
SR.sup.37, S(O)R.sup.37, SO.sub.2R.sup.37, NHR.sup.37 or
N(R.sup.32)R.sup.37;
R.sup.26 is phenyl which is unfused or fused with arene or
heteroarene;
R.sup.27 is heteroarene which is unfused or fused with arene or
heteroarene;
R.sup.28 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.28A; R.sup.28A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene
R.sup.29 is heteroaryl or R.sup.29A; R.sup.29A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.30 is cycloalkyl or cycloalkenyl, each having one or two
CH.sub.2 moieties unreplaced or replaced with independently
selected O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and
one or two CH moieties unreplaced or replaced with N, and each of
which is unfused or fused with arene, heteroarene or R.sup.30A;
R.sup.30A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.31 and R.sup.31A are independently F, Cl, Br or alkyl or are
taken together and are C.sub.2-C.sub.5-spiroalkyl;
R.sup.32 is R.sup.33, C(O)R.sup.33 or C(O)OR.sup.33;
R.sup.33 is R.sup.34 or R.sup.35;
R.sup.34 is phenyl which is unfused or fused with aryl, heteroaryl
or R.sup.34A; R.sup.34A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.35 is alkyl which is unsubstituted or substituted with
R.sup.36;
R.sup.36 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.36A; R.sup.36A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.37 is R.sup.38, R.sup.39 or R.sup.40, each of which is
substituted with F, Cl, Br, I, R.sup.41, OR.sup.41, NHR.sup.41,
N(R.sup.41).sub.2, NHC(O)OR.sup.41, SR.sup.41, S(O)R.sup.41 or
SO.sub.2R.sup.41;
R.sup.38 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.38A; R.sup.38A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.39 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.39A; R.sup.39A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.40 is C.sub.3-C.sub.5-cycloalkyl or
C.sub.4-C.sub.8-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.40A; R.sup.40A
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.41 is R.sup.42, R.sup.43, R.sup.44 or R.sup.45;
R.sup.42 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.42A; R.sup.42A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.43 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.43A; R.sup.43A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.44 is C.sub.3-C.sub.9-cycloalkyl or
C.sub.4-C.sub.7-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.44A; R.sup.44 is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.45 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two independently selected
R.sup.46, OR.sup.46, NHR.sup.46, N(R.sup.46).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.46, C(O)N(R.sup.46).sub.2, OH, (O), C(O)OH, N.sub.3,
CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
R.sup.46 is R.sup.47, R.sup.48 or R.sup.49;
R.sup.47 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.47A; R.sup.47A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.48 is heteroaryl or R.sup.48A; R.sup.48A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.49 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.49A; R.sup.49A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
wherein the moieties represented by R.sup.16 and R.sup.27 are
further substituted by one or two or three of independently
selected R.sup.50A, OR.sup.50A, SR.sup.50A, S(O)R.sup.50A
SO.sub.2R.sup.50A or NHR.sup.50A,
R.sup.50A is R.sup.51A, R.sup.52A, R.sup.53A or R.sup.54A;
R.sup.51A is phenyl which is unfused or fused with benzene,
heteroarene or R.sup.51AA;
wherein R.sup.51AA is cycloalkane, cycloalkene or heterocycloalkane
heterocycloalkene,
R.sup.52A is heteroaryl;
R.sup.53A is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl; each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.53AA;
wherein R.sup.53AA is cycloalkane, cycloalkene, heterocycloalkane
or heterocycloalkene;
R.sup.54A is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.55AA, OR.sup.55AA, SR.sup.55AA,
S(O)R.sup.55AA, SO.sub.2R.sup.55AA, NHR.sup.55AA, N(R.sup.55AA),
C(O)R.sup.55AA, C(O)NH.sub.2, C(O)NHR.sup.55AA, NHC(O)R.sup.55AA,
NHSO.sub.2R.sup.55AA, NHC(O)OR.sup.55AA, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.55AA, SO.sub.2N(R.sup.55AA).sub.2, NHC(O)NH.sub.2,
NHC(O)NHR.sup.55AA, OH, (O), C(O)OH, (O), N.sub.3, CN, NH.sub.2,
CF.sub.3, OCF.sub.3, CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br
or I substituents;
R.sup.55AA is alkyl, alkenyl, alkynyl, phenyl or heteroaryl, or
R.sup.56A;
R.sup.56A is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N;
wherein moieties represented by R.sup.2, R.sup.3R.sup.4, R.sup.6,
R.sup.6C, R.sup.8, R.sup.8AR.sup.9, R.sup.10, R.sup.13, R.sup.14,
R.sup.15, R.sup.18, R.sup.19, R.sup.20, R.sup.23, R.sup.24,
R.sup.25, R.sup.26, R.sup.27, R.sup.28, R.sup.29, R.sup.30,
R.sup.34, R.sup.36, R.sup.38, R.sup.39, R.sup.40, R.sup.42,
R.sup.43, R.sup.44, R.sup.47, R.sup.48, and R.sup.49 are
independently unsubstituted, further unsubstituted, substituted or
further substituted with one or two or three or four or five
independently selected R.sup.50, OR.sup.50, SR.sup.50,
S(O)R.sup.50, SO.sub.2R.sup.50, C(O)R.sup.50, CO(O)R.sup.50,
OC(O)R.sup.50, OC(O)OR.sup.50, NH.sub.1, NHR.sup.50,
N(R.sup.50).sub.2, C(O)NH.sub.2, C(O)NHR.sup.50,
C(O)N(R.sup.50).sub.2, C(O)NHOH, C(O)NHOR.sup.50,
C(O)NHSO.sub.2R.sup.50, C(O)NR.sup.55SO.sub.2R.sup.50,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.50, SO.sub.2N(R.sup.50).sub.2,
CF.sub.3, CF.sub.2CF.sub.3, C(O)H, C(O)OH, C(N)NH.sub.2,
C(N)NHR.sup.50, C(N)N(R.sup.50).sub.2, OH, (O), CN, N.sub.3,
NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3,
F, Cl, Br or I substituents;
R.sup.50 is R.sup.51, R.sup.52, R.sup.53 or R.sup.54,
R.sup.51 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.51B; R.sup.51B is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.52 is heteroaryl;
R.sup.53 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.53B;
wherein R.sup.53B is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.54 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.55, OR.sup.55, SR.sup.55, S(O)R.sup.55,
SO.sub.2R.sup.55, NHR.sup.55, N(R.sup.55).sub.2, C(O)R.sup.55,
C(O)NH.sub.2, C(O)NHR.sup.55, NHC(O)R.sup.55, NHSO.sub.2R.sup.55,
NHC(O)OR.sup.55, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.55,
SO.sub.2N(R.sup.55).sub.2, NHC(O)NH.sub.2, NHC(O)NHR.sup.55, OH,
(O), C(O)OH, (O), N.sub.3, CN, NH.sub.2, CF.sub.3, OCF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
R.sup.55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or
R.sup.56; and
wherein the alkyl, alkenyl, alkynyl are unsubstituted or
substituted with OCH.sub.3; and
R.sup.56 is C.sub.3-C.sub.5-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N.
Another embodiment of this invention pertains to compounds of
Formula (I), wherein wherein A.sup.1 is N or C(A.sup.2);
one or two or three or each of A.sup.2, B.sup.1, D.sup.1 and
E.sup.1 are independently selected R.sup.1, OR.sup.1, SR.sup.1,
S(O)R.sup.1, SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1,
OC(O)R.sup.1, NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1,
C(O)N(R.sup.1).sub.2, NHC(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)NHR.sup.1, NR.sup.1C(O)N(R.sup.1).sub.2,
SO.sub.2NHR.sup.1, SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NHSO.sub.2NHR.sup.1 or N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, and
the remainder are independently selected H, F, Cl, Br, I, CN,
CF.sub.3, C(O)OH, C(O)NH.sub.2 or C(O)OR.sup.1A; and
Y.sup.1 is H, CN, NO.sub.2, C(O)OH, F, Cl, Br, I, CF.sub.3,
OCF.sub.3, CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, R.sup.17,
OR.sup.17, C(O)R.sup.17, C(O)OR.sup.17, SR.sup.17, NH.sub.2,
NHR.sup.17, N(R.sup.17).sub.2, NHC(O)R.sup.17, C(O)NH.sub.2,
C(O)NHR.sup.17, C(O)N(R.sup.17).sub.2, NHS(O)R.sup.17 or
NHSO.sub.2R.sup.17;
or
B.sup.1 and Y.sup.1, together with the atoms to which they are
attached, are imidazole or triazole; and
one or two or each of A.sup.2, D.sup.1 and E.sup.1 are
independently selected R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NHC(O)OR.sup.1, NHC(O)NHR.sup.1,
N(CH.sub.3)C(O)N(CH.sub.3)R.sup.1, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1 or
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, and the remainder are
independently selected H, F, Cl, Br, I, CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
R.sup.1 is R.sup.2, R.sup.3, R.sup.4 or R.sup.5;
R.sup.1A is C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-alkenyl or
C.sub.3-C.sub.6-alkynyl;
R.sup.2 is phenyl which is unfused or fused with arene, heteroarene
or R.sup.2A; R.sup.2A is cycloalkane or heterocycloalkane;
R.sup.3 is heteroaryl which is unfused or fused with benzene,
heteroarene or R.sup.3A; R.sup.3A is cycloalkane or
heterocycloalkane;
R.sup.4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with arene,
heteroarene or R.sup.4A; R.sup.4A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.5 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.6, NC(R.sup.6A)(R.sup.6B), R.sup.7, OR.sup.7,
SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7, NHR.sup.7,
N(R.sup.7).sub.2, C(O)R.sup.7, C(O)NH.sub.2, C(O)NHR.sup.7,
NHC(O)R.sup.7, NHSO.sub.2R.sup.7, NHC(O)OR.sup.7, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2, NHC(O)NH.sub.2,
NHC(O)NHR.sup.7, NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NH.sub.2,
NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NHR.sup.7, OH, (O), C(O)OH,
(O), N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br
or I substituents;
R.sup.6 is C.sub.2-C.sub.5-spiroalkyl, each of which is
unsubstituted or substituted with OH, (O), N.sub.3, CN, CF.sub.3,
CF.sub.2CF.sub.3, F, Cl, Br, I, NH.sub.2, NH(CH.sub.3) or
N(CH.sub.3).sub.2;
R.sup.6A and R.sup.6B are independently selected alkyl or, together
with the N to which they are attached, R.sup.6C;
R.sup.6C is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl or
piperidin-1-yl, each having one CH.sub.2 moiety unreplaced or
replaced with O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2, nor
NH;
R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
R.sup.8 is phenyl which is unfused or fused with arene, heteroarene
or R.sup.8A;
R.sup.8A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.9 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.9A; R.sup.9A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.10 is C.sub.3-C.sub.10-cycloalkyl or
C.sub.4-C.sub.10-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.10A; R.sup.10A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.11 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.12, OR.sup.12, NHR.sup.12, N(R.sup.12).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.12, C(O)N(R.sup.12).sub.2, OH, (O),
C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl,
Br or I substituents;
R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16;
R.sup.13 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.13A; R.sup.13A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.14 is heteroaryl, each of which is unfused or fused with
arene, heteroarene or R.sup.14A;
R.sup.14A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.15 is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene, each of which is unfused or fused with arene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.16 is alkyl, alkenyl or alkynyl;
R.sup.17 is R.sup.18, R.sup.19, R.sup.20 or R.sup.21,
R.sup.18 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.18A; R.sup.18A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.19 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.19A; R.sup.19A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.20 is C.sub.3-C.sub.10-cycloalkyl or
C.sub.4-C.sub.10-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.20A; R.sup.20A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.21 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.22, OR.sup.22, NHR.sup.22, N(R.sup.22).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.22, C(O)N(R.sup.22).sub.2, OH, (O),
C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl,
Br or I substituents;
R.sup.22 is R.sup.23, R.sup.24 or R.sup.25;
R.sup.23 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.23A; R.sup.23A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.24 is heteroarene which is unfused or fused with arene,
heteroarene or R.sup.24A; R.sup.24A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.25 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.25A; R.sup.25A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
Z.sup.1 is R.sup.26 or R.sup.27, each of which is substituted with
R.sup.28, R.sup.29 or R.sup.30, each of which is substituted with
F, Cl, Br, I, CH.sub.2R.sup.37, CH(R.sup.31)(R.sup.37),
C(R.sup.31)(R.sup.31A)(R.sup.37), C(O)R.sup.37, OR.sup.37,
SR.sup.37, S(O)R.sup.37, SO.sub.2R.sup.37, NHR.sup.37 or
N(R.sup.32)R.sup.37;
R.sup.26 is phenyl which is unfused or fused with arene or
heteroarene;
R.sup.27 is heteroarene which is unfused or fused with arene or
heteroarene;
R.sup.28 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.28A; R.sup.28A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene
R.sup.29 is heteroaryl or R.sup.29A; R.sup.29A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.30 is cycloalkyl or cycloalkenyl, each having one or two
CH.sub.2 moieties unreplaced or replaced with independently
selected O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and
one or two CH moieties unreplaced or replaced with N, and each of
which is unfused or fused with arene, heteroarene or R.sup.30A;
R.sup.30A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.31 and R.sup.31A are independently F, Cl, Br or alkyl or are
taken together and are C.sub.2-C.sub.5-spiroalkyl;
R.sup.32 is R.sup.33, C(O)R.sup.33 or C(O)OR.sup.33;
R.sup.33 is R.sup.34 or R.sup.35;
R.sup.34 is phenyl which is unfused or fused with aryl, heteroaryl
or R.sup.34A; R.sup.34A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.35 is alkyl which is unsubstituted or substituted with
R.sup.36;
R.sup.36 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.36A; R.sup.36A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.37 is R.sup.38, R.sup.39 or R.sup.40, each of which is
substituted with F, Cl, Br, I, R.sup.41, OR.sup.41, NHR.sup.41,
N(R.sup.41).sub.2, NHC(O)OR.sup.41, SR.sup.41, S(O)R.sup.41 or
SO.sub.2R.sup.41;
R.sup.38 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.38A; R.sup.38A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.39 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.39A; R.sup.39A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.40 is C.sub.3-C.sub.5-cycloalkyl or
C.sub.4-C.sub.8-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.40A; R.sup.40A
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.41 is R.sup.42, R.sup.43, R.sup.44 or R.sup.45;
R.sup.42 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.42A; R.sup.42A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.43 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.43A; R.sup.43A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.44 is C.sub.3-C.sub.9-cycloalkyl or
C.sub.4-C.sub.7-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.44A; R.sup.44A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.45 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two independently selected
R.sup.46, OR.sup.46, NHR.sup.46, N(R.sup.46).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.46, C(O)N(R.sup.46).sub.2, OH, (O), C(O)OH, N.sub.3,
CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
R.sup.46 is R.sup.47, R.sup.48 or R.sup.49;
R.sup.47 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.47A; R.sup.47A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.48 is heteroaryl or R.sup.48A; R.sup.48A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.49 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.49A; R.sup.49A is
cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
wherein the moieties represented by R.sup.26 and R.sup.27 are
further substituted with OR.sup.50A,
R.sup.50A is R.sup.51A;
R.sup.51A is phenyl which is fused with heteroarene;
wherein moieties represented by R.sup.2R.sup.3R.sup.4, R.sup.6,
R.sup.6C, R.sup.8, R.sup.8AR.sup.9, R.sup.10, R.sup.13, R.sup.14,
R.sup.15, R.sup.18, R.sup.19, R.sup.20, R.sup.23, R.sup.24,
R.sup.25, R.sup.26, R.sup.27, R.sup.28, R.sup.29, R.sup.30,
R.sup.34, R.sup.36, R.sup.38, R.sup.39, R.sup.40, R.sup.42,
R.sup.43, R.sup.44, R.sup.47, R.sup.48, and R.sup.49 are
independently unsubstituted, further unsubstituted, substituted or
further substituted with one or two or three or four or five
independently selected R.sup.50, OR.sup.50, SR.sup.50,
S(O)R.sup.50, SO.sub.2R.sup.50, C(O)R.sup.50, CO(O)R.sup.50,
OC(O)R.sup.50, OC(O)OR.sup.50, NH.sub.2, NHR.sup.50,
N(R.sup.50).sub.2, C(O)NH.sub.2, C(O)NHR.sup.50,
C(O)N(R.sup.50).sub.2, C(O)NHOH, C(O)NHOR.sup.50,
C(O)NHSO.sub.2R.sup.50, C(O)NR.sup.55SO.sub.2R.sup.50,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.50, SO.sub.2N(R.sup.50).sub.2,
CF.sub.3, CF.sub.2CF.sub.3, C(O)H, C(O)OH, C(N)NH.sub.2,
C(N)NHR.sup.50, C(N)N(R.sup.50).sub.2, OH, (O), CN, N.sub.3,
NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3,
F, Cl, Br or I substituents;
R.sup.50 is R.sup.51, R.sup.52, R.sup.53 or R.sup.54;
R.sup.51 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.51B; R.sup.51B is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.52 is heteroaryl;
R.sup.53 is C.sub.3-C.sub.6-cycloalkyl or
C.sub.4-C.sub.6-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties unreplaced or replaced with N, and each of which is
unfused or fused with arene, heteroarene or R.sup.53B;
wherein R.sup.53B is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
R.sup.54 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected R.sup.55, OR.sup.55, SR.sup.55, S(O)R.sup.55,
SO.sub.2R.sup.55, NHR.sup.55, N(R.sup.55).sub.2, C(O)R.sup.55,
C(O)NH.sub.2, C(O)NHR.sup.55, NHC(O)R.sup.55, NHSO.sub.2R.sup.55,
NHC(O)OR.sup.55, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.55,
SO.sub.2N(R.sup.55).sub.2, NHC(O)NH.sub.2, NHC(O)NHR.sup.55, OH,
(O), C(O)OH, (O), N.sub.3, CN, NH.sub.2, CF.sub.3, OCF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
R.sup.55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or
R.sup.56; and wherein the alkyl, alkenyl, alkynyl are unsubstituted
or substituted with OCH.sub.3; and R.sup.56 is
C.sub.3-C.sub.8-cycloalkyl or C.sub.4-C.sub.6-cycloalkenyl, each
having one or two CH.sub.2 moieties unreplaced or replaced with
independently selected O, C(O), CNOH, CNOCH.sub.3, S, S(O),
SO.sub.2 or NH and one or two CH moieties unreplaced or replaced
with N.
In one embodiment of Formula (I), A is N or C(A.sup.2);
one or two or three or each of A.sup.2, B.sup.1, D.sup.1 and
E.sup.1 are independently selected R.sup.1, OR.sup.1, SR.sup.1,
SO.sub.2R.sup.1, NHR.sup.1, N(R.sup.1).sub.2, or C(O)NHR.sup.1, and
the remainder are independently selected H, F, Cl, Br, or I;
Y.sup.1 is H, CN, NO.sub.2, F, Cl, Br, I, CF.sub.3, R.sup.17,
NHC(O)R.sup.17, or C(O)NH.sub.2;
R.sup.1 is R.sup.2, R.sup.3, R.sup.4 or R.sup.5;
R.sup.2 is phenyl;
R.sup.3 is heteroaryl;
R.sup.4 is cycloalkyl, heterocycloalkyl or heterocycloalkenyl, each
of which is unfused or fused with R.sup.4A; R.sup.4A is
cycloalkane;
R.sup.5 is alkyl, or alkynyl, each of which is unsubstituted or
substituted with one or two or three independently selected
R.sup.6, R.sup.7, OR.sup.7, SR.sup.7, SO.sub.2R.sup.7,
N(R.sup.7).sub.2, OH, CN, CF.sub.3, F, Cl, Br or I
substituents;
R.sup.6 is C.sub.2-C.sub.5-spiroalkyl;
R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
R.sup.8 is phenyl which is unfused or fused with R.sup.8A;
R.sup.8A is heterocycloalkane;
R.sup.9 is heteroaryl;
R.sup.10 is C.sub.3-C.sub.10-cycloalkyl, each having one or two
CH.sub.2 moieties unreplaced or replaced with independently
selected O, S(O), SO.sub.2 or NH and one or two CH moieties
unreplaced or replaced with N;
R.sup.11 is alkyl, each of which is unsubstituted or substituted
with one or two or three independently selected OR.sup.12, F, Cl,
Br or I substituents;
R.sup.12 is R.sup.16;
R.sup.16 is alkyl;
R.sup.17 is R.sup.19 or R.sup.21;
R.sup.19 is heteroaryl which is unfused or fused with arene,
heteroarene or R.sup.19A; R.sup.19A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
R.sup.21 is alkynyl;
Z.sup.1 is R.sup.26, each of which is substituted with R.sup.30,
each of which is substituted with F, Cl, Br, I, CH.sub.2R.sup.37,
or CH(R.sup.31)(R.sup.37);
R.sup.26 is phenyl;
R.sup.30 is cycloalkyl, each having two CH.sub.2 moieties
unreplaced or replaced with NH;
R.sup.31 and R.sup.31A are independently alkyl;
R.sup.37 is R.sup.38, R.sup.39 or R.sup.40, each of which is
substituted with F, Cl, Br, I, NHR.sup.41, or R.sup.41;
R.sup.38 is phenyl;
R.sup.39 is heteroaryl;
R.sup.40 is C.sub.3-C.sub.8-cycloalkyl or
C.sub.4-C.sub.8-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH;
R.sup.41 is R.sup.42, R.sup.43, or R.sup.44;
R.sup.42 is phenyl;
R.sup.43 is heteroaryl;
R.sup.44 is C.sub.3-C.sub.9-cycloalkyl or
C.sub.4-C.sub.7-cycloalkenyl, each having one or two CH.sub.2
moieties unreplaced or replaced with independently selected NH and
one or two CH moieties unreplaced or replaced with N, and each of
which is unfused or fused with R.sup.44A; R.sup.44A is
cycloalkane;
wherein the moiety represented by R.sup.26 is further substituted
by one or two or three of independently selected R.sup.50A,
OR.sup.50A, SR.sup.50A, S(O)R.sup.50A, SO.sub.2R.sup.50A or
NHR.sup.50A;
R.sup.50A is R.sup.51A, R.sup.52A or R.sup.54A;
R.sup.51A is phenyl which is unfused or fused with benzene,
heteroarene or R.sup.51AA; wherein R.sup.51AA is
heterocycloalkane;
R.sup.152A is heteroaryl;
R.sup.54A is alkyl, each of which is unsubstituted or substituted
with one or two or three of independently selected R.sup.55AA, or
OR.sup.55AA;
R.sup.55AA is phenyl;
wherein moieties represented by R.sup.2R.sup.3R.sup.4, R.sup.6,
R.sup.6C, R.sup.8, R.sup.8AR.sup.9, R.sup.10, R.sup.13, R.sup.4,
R.sup.15, R.sup.18, R.sup.19, R.sup.20, R.sup.23, R.sup.24,
R.sup.25, R.sup.26, R.sup.27, R.sup.28, R.sup.29, R.sup.30,
R.sup.34, R.sup.36, R.sup.38, R.sup.39, R.sup.40, R.sup.42,
R.sup.43, R.sup.44, R.sup.47, R.sup.48, and R.sup.49 are
independently unsubstituted, further unsubstituted, substituted or
further substituted with one or two or three or four or five
independently selected R.sup.50, OR.sup.50, SR.sup.50,
S(O)R.sup.50, SO.sub.2R.sup.50, C(O)R.sup.50, CO(O)R.sup.50,
NH.sub.2, NHR.sup.50, SO.sub.2NH.sub.2, OH, (O), CN, CF.sub.3,
OCF.sub.3, F, Cl, Br or I substituents;
R.sup.50 is R.sup.51, R.sup.52, or R.sup.54;
R.sup.51 is phenyl which is unfused or fused with arene,
heteroarene or R.sup.51B; R.sup.51B is heterocycloalkane;
R.sup.52 is heteroaryl;
R.sup.53 is C.sub.3-C.sub.6-cycloalkyl, each having one or two
CH.sub.2 moieties unreplaced or replaced with independently
selected O, and one or two CH moieties unreplaced or replaced with
N;
R.sup.54 is alkyl, each of which is unsubstituted or substituted
with one or two or three independently selected R.sup.55,
OR.sup.55, N(R.sup.55).sub.2, OH, CN, F, Cl, Br or I substituents;
and R.sup.55 is alkyl or phenyl;
wherein the alkyl is unsubstituted or substituted with OCH.sub.3;
and
R.sup.56 is C.sub.3-C.sub.8-cycloalkyl, each having one or two
CH.sub.2 moieties unreplaced or replaced with independently
selected NH and one or two CH moieties unreplaced or replaced with
N.
In one embodiment of Formula (I), A.sup.1 is N. In another
embodiment of Formula (I), A.sup.1 is C(A.sup.2). In another
embodiment of Formula (I), A.sup.1 is C(A.sup.2), and A.sup.2 is
H.
In one embodiment of Formula (I), B.sup.1 is R.sup.1, OR.sup.1,
SR.sup.1, SO.sub.2R.sup.1, NHR.sup.1, N(R.sup.1).sub.2, or
C(O)NHR.sup.1. In another embodiment of Formula (I), B.sup.1 is
NHR.sup.1. In another embodiment of Formula (I), B.sup.1 is
NHR.sup.1, and A.sup.1 is C(A.sup.2), and A.sup.2 is H. In another
embodiment of Formula (I), B.sup.1 is OR.sup.1. In another
embodiment of Formula (I), B.sup.1 is OR.sup.1, and A.sup.1 is
C(A.sup.2), and A.sup.2 is H.
In one embodiment of Formula (I), D.sup.1 and E.sup.1 are H. In
another embodiment of Formula (I), B.sup.1 is NHR.sup.1, and
A.sup.1 is C(A.sup.2), A.sup.2 is H, and D.sup.1 and E.sup.1 are H.
In another embodiment of Formula (I), B.sup.1 is OR.sup.1, and
A.sup.1 is C(A.sup.2), A.sup.2 is H, and D.sup.1 and E.sup.1 are
H.
In one embodiment of Formula (I), Y.sup.1 is H, CN, NO.sub.2, F,
Cl, Br, I, CF.sub.3, R.sup.7, NHC(O)R.sup.17, or C(O)NH.sub.2. In
another embodiment of Formula (I), Y.sup.1 is NO.sub.2. In another
embodiment of Formula (I), Y.sup.1 is Cl. In another embodiment of
Formula (I), B.sup.1 is NHR.sup.1, and A.sup.1 is C(A.sup.2),
A.sup.2 is H, D.sup.1 and E.sup.1 are H, and Y.sup.1 is NO.sub.2.
In another embodiment of Formula (I), B.sup.1 is OR.sup.1, and
A.sup.1 is C(A.sup.2), A.sup.2 is H, D.sup.1 and E.sup.1 are H, and
yl is Cl.
In one embodiment of Formula (I), R.sup.1 is R.sup.2, R.sup.3,
R.sup.4 or R.sup.5. In another embodiment of Formula (I), R.sup.1
is R.sup.2, and R.sup.2 is phenyl.
In one embodiment of Formula (I), R.sup.1 is R.sup.3, and R.sup.3
is heteroaryl. In another embodiment of Formula (I), R.sup.3 is
triazolyl.
In one embodiment of Formula (I), R.sup.1 is R.sup.4. In another
embodiment of Formula (I), R.sup.1 is R.sup.4, and R.sup.4 is
cycloalkyl. In another embodiment of Formula (I), R.sup.1 is
R.sup.4, and R.sup.4 is cyclohexyl. In another embodiment of
Formula (I), R.sup.1 is R.sup.4, and R.sup.4 is heterocycloalkyl.
In another embodiment of Formula (I), R.sup.1 is R.sup.4, and
R.sup.4 is 8-azabicyclo[3.2.1]octane, azetidinyl, piperidinyl,
piperazinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, or
tetrahydrothiophenyl. In another embodiment of Formula (I), R.sup.1
is R.sup.4, and R.sup.4 is heterocycloalkenyl. In another
embodiment of Formula (I), R.sup.1 is R.sup.4, and R.sup.4 is
tetrahydropyridazinyl.
In one embodiment of Formula (I), R.sup.1 is R.sup.5. In another
embodiment of Formula (I), R.sup.1 is R.sup.5 and R.sup.5 is alkyl
or alkynyl. In another embodiment of Formula (I), R.sup.1 is
R.sup.5 and R.sup.5 is alkyl which is unsubstituted. In another
embodiment of Formula (I), R.sup.1 is R.sup.5 and R.sup.5 is alkyl
which is substituted with one or two or three independently
selected R.sup.6, R.sup.7, OR.sup.7, SR.sup.7, SO.sub.2R.sup.7,
N(R.sup.7).sub.2, OH, CN, CF.sub.3, F, Cl, Br or I substituents. In
another embodiment of Formula (I), R.sup.1 is R.sup.5 and R.sup.5
is alkyl which is substituted with R.sup.7.
In one embodiment of Formula (I), R.sup.7 is R.sup.8, R.sup.9,
R.sup.10 or R.sup.11. In another embodiment of Formula (I), R.sup.7
is R.sup.8, and R.sup.8 is phenyl which is unfused or fused with
R.sup.8A, and R.sup.8A is heterocycloalkane. In another embodiment
of Formula (I), R.sup.7 is R.sup.8, and R.sup.8 is phenyl which is
unfused. In another embodiment of Formula (I), R.sup.7 is R.sup.9,
and R.sup.9 is heteroaryl. In another embodiment of Formula (I),
R.sup.7 is R.sup.9, and R.sup.9 is furanyl, imidazolyl,
isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl,
oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl,
pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl
or 1,2,3-triazolyl. In another embodiment of Formula (I), R.sup.7
is R.sup.9, and R.sup.9 is pyridinyl, thiazolyl, imidazoyl, and
1,2,3-triazolyl. In another embodiment of Formula (I), R.sup.7 is
R.sup.10, and R.sup.10 is C.sub.3-C.sub.10-cycloalkyl. In another
embodiment of Formula (I), R.sup.7 is R.sup.10, and R.sup.10 is
C.sub.6 or C.sub.10-cycloalkyl. In another embodiment of Formula
(I), R.sup.7 is R.sup.10, and R.sup.10 is cyclohexyl or
adamantanyl. In another embodiment of Formula (I), R.sup.7 is
R.sup.10, and R.sup.10 is morpholinyl, piperazinyl, piperidinyl,
tetrahydro-2H-pyranyl, 1,2-dihydropyridinyl, pyranyl,
pyridin-1(H)-yl, pyrrolidinyl, oxetanyl, thiomorpholinyl,
imidazolidinyl, tetrahydrothiophenyl, dioxolanyl,
tetrahydrothiopyranyl, dioxanyl, or tetrahydrofuranyl. In another
embodiment of Formula (I), R.sup.7 is R.sup.10, and R.sup.10 is
morpholinyl, piperazinyl, piperidinyl, tetrahydro-2H-pyranyl,
1,2-dihydropyridinyl, pyrrolidinyl, oxetanyl, thiomorpholinyl,
imidazolidinyl, tetrahydrothiophenyl, dioxolanyl,
tetrahydrothiopyranyl, dioxanyl, or tetrahydrofuranyl. In another
embodiment of Formula (I), R.sup.7 is R.sup.11, and R.sup.11 is
alkyl which is unsubstituted or substituted. In another embodiment
of Formula (I), R.sup.7 is R.sup.11, and R.sup.11 is alkyl which is
unsubstituted. In another embodiment of Formula (I), R.sup.7 is
R.sup.11, and R.sup.11 is alkyl which is substituted. In another
embodiment of Formula (I), R.sup.7 is R.sup.11, and R.sup.11 is
alkyl which is substituted with one or two or three independently
selected OR.sup.12, F, Cl, Br or I substituents.
In another embodiment of Formula (I), R.sup.7 is R.sup.11, R.sup.11
is alkyl which is substituted with OR.sup.2, R.sup.12 is R.sup.16,
and R.sup.16 is alkyl.
In one embodiment of Formula (I), R.sup.17 is R.sup.19 or R.sup.21.
In another embodiment of Formula (I), R.sup.17 is R.sup.19, and
R.sup.19 is heteroaryl. In another embodiment of Formula (I),
R.sup.17 is R.sup.19, and R.sup.19 is thiazolyl. In another
embodiment of Formula (I), R.sup.17 is R.sup.1, and R.sup.2 is
alkynyl. In another embodiment of Formula (I), R.sup.17 is
R.sup.21, and R.sup.21 is ethynyl.
Still another embodiment pertains to compounds having Formula I
which are
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide-
; benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((-
4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;
2-(benzyloxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)--
N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benza-
mide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nit-
ro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(2-phenylet-
hoxy)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenylthio)benz-
amide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(pheny-
lthio)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzam-
ide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3--
morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(phenylthio)benzamid-
e;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro--
4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenylsulfony-
l)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenylsulfinyl)-
benzamide;
2-benzyl-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-
-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-
benzamide;
2-benzyl-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-
-yl)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamid-
e;
2-benzyl-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-(-
(4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-5-(2-phenylethyl)b-
enzamide;
2-(benzylamino)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sul-
fonyl)benzamide;
2-anilino-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((-
34-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamid-
e;
2-anilino-4-(4-((4'-chloro-1'-biphenyl-2-yl)methyl)piperazin-1-yl)N-((4-
-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-methoxy-N-((-
3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide-
;
4-(4-((2-(4-chlorophenyl)-4,54-dimethylcyclohex-1-en-1-yl)methyl)piperaz-
in-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-p-
henoxybenzamide;
4-(4-((2-(4-chlorophenyl)-5,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indazol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitr-
ophenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indazol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitr-
ophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((4-(morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(1,2,3-
,4-tetrahydroquinolin-6-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(1,-
2,3,4-tetrahydroquinolin-6-yloxy)benzamide;
4-(4-((4'-chloro-4-(pyrrolidin-1-ylmethyl)-1,1'-biphenyl-2-yl)methyl)pipe-
razin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylm-
ethyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl-
methyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((1-cyclopentylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)--
2-(1H-indol-5-yloxy)benzamide
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)-3-isobutylpiperazin-1-yl)-N-(-
(3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-pheno-
xybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(2,4-dio-
xo-3-azabicyclo(3.2.0)hept-3-yl)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(4-methy-
l-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)sulfonyl)-2-phenoxybenzami-
de;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(3,3--
dimethyl-2-oxoazetidin-1-yl)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(4-nitro--
2H-1,2,3-triazol-2-yl)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((-
2-(2-piperidin-1-ylethoxy)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-((((1-et-
hylpyrrolidin-2-yl)methyl)amino)carbonyl)-4-methoxyphenyl)sulfonyl)-2-phen-
oxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1-naphthylo-
xy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)b-
enzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2--
naphthyloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)s-
ulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morp-
holin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-naphthyloxy)benzamide-
;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-naphthyl-
oxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sul-
fonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((-
tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(quinolin-7-yloxy)-
benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((-
3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(quino-
lin-6-yloxy)benzamide;
4-(4-((4'-chloro-1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yl-
oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-
benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(i-
soquinolin-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)p-
henyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(isoquinolin-5-yloxy)be-
nzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4--
((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(quinolin-6-ylo-
xy)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benza-
mide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-ind-
ol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)su-
lfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino) 3
nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-6-yloxy)benza-
mide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(isoqui-
nolin-7-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfony-
l)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(isoquinolin-7-yloxy)be-
nzamide;
4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)p-
iperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)--
3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1-
H-indol-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrop-
henyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(H-
-indol-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrop-
henyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrop-
henyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1-
H-indol-4-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1-
H-indol-4-yloxy)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4--
yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzam-
ide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indo-
l-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)be-
nzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4--
methoxyphenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-methylph-
enyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5--
yloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)s-
ulfonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4--
yloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)s-
ulfonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-2-(-
1H-indol-5-yloxy)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4--
yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-((trifluoromethyl)sulfonyl)-
phenyl)sulfonyl)benzamide;
N-((3-((chloro(difluoro)methyl)sulfonyl)-4-((3-(dimethylamino)propyl)amin-
o)phenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-y-
l)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;
2-(1H-indol-4-yloxy)-4-(4-((2-(4-methoxyphenyl)-4,4-dimethylcyclohex-1-en-
-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino-
)phenyl)sulfonyl)benzamide;
4-(4-((4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)cyclohex-1-en-1-yl)methy-
l)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpr-
opyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4,4-dimethyl-2-(4-(trifluoromethoxy)phenyl)cyclohex-1-en-1-yl)meth-
yl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylp-
ropyl)amino)phenyl)sulfonyl)benzamide; 4-(4-((4,
4-dimethyl-2-(3-(trifluoromethyl)phenyl)cyclohex-1-en-1-yl)methyl)piperaz-
in-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amin-
o)phenyl)sulfonyl)benzamide;
4-(4-((2-(3-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)-
phenyl)sulfonyl)benzamide;
4-(4-((2-(4-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)-
phenyl)sulfonyl)benzamide;
N-((3-((chloro(difluoro)methyl)sulfonyl)-4-((1-methylpiperidin-4-yl)amino-
)phenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl-
)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1-i-
ndol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl-
)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-((trif-
luoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenoxymethyl)b-
enzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-
-((3-morpholin-4-ylpropyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(pyridin-3-yloxy-
)benzamide;
4-(4-((4-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(pyridin-3-yl-
oxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamid-
e;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(((1R)-
-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfo-
nyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(pyridin-4-yloxy-
)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morp-
holin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(pyridin-3-yloxy)benzami-
de;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-m-
orpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(pyridin-4-yloxy)benz-
amide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((-
2-(4-methylpiperazin-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybe-
nzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4--
((3-(4-methylpiperazin-1-yl)propyl)amino)-3-nitrophenyl)sulfonyl)-2-phenox-
ybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)(methyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamid-
e;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(((1-m-
ethylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzami-
de;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((1-m-
ethylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-cyano-4--
((3-(dimethylamino)propyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-(trifluoromethyl)phenyl)sulfonyl)-2-phenoxybenz-
amide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((-
3-(isopropyl(methyl)amino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxyb-
enzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-
-(3-(dimethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-
-3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-(4-methylpiperazin-1-yl)propyl)amino-
)-3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)-
phenyl)sulfonyl)benzamide
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrop-
henyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-(4-methylpiperazin-1-yl)propyl)amino-
)-3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-(3-(dimethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-(1H-indo-
l-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-
-3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)-
phenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrop-
henyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)--
3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)--
3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-(3-(dimethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-(1H-indo-
l-4-yloxy)benzamide; 4-(4
((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl-
)-2-(1H-indol-5-yloxy)-N-((4-(4-methylpiperazin-1-yl)-3-nitrophenyl)sulfon-
yl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((1-(2,2,2-trifluoroethyl)piperi-
din-4-yl)amino)phenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-(((4-(dimethylamino)-1-methylpiperidin-4-yl)methyl)amino)-3-n-
itrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydro-
-1,4-benzodioxin-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)a-
mino)phenyl)sulfonyl)benzamide;
5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-1,1'-biphenyl-2-ca-
rboxamide;
5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((-
4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-1,1'-biphenyl-2-
-carboxamide;
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)-
sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-4-(3-piperidin-1-ylpropoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)-
sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)s-
ulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-4-(3-(dimethylamino)propoxy)-1,1'-biphenyl-2-yl)methyl)p-
iperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl-
)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((t-
rifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(3-piperidin-1-ylpropoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((-
trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(3-(dimethylamino)propoxy)-1,1'-biphenyl-2-yl)methyl)p-
iperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-(-
(trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((-
trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfony-
l)-2-phenoxybenzamide;
4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)-
sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfony-
l)-2-phenoxybenzamide;
4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((-
trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-y-
lmethyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-y-
lmethyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl-
methyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-y-
lmethyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-y-
lmethyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl-
methyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-3-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl-
methyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-3-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl-
methyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl-
)-2-phenoxybenzamide;
4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl-
)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl-
)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)-
amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-N-((3-nitro-4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino-
)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-4-(2-pyrrolidin-1-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)-
sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-4-(2-(diisopropylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl-
)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phen-
yl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydro-
-1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)ph-
enyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-
-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfo-
nyl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclooct-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H--
indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfon-
yl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-
-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfo-
nyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en-1-yl)methyl)piperazi-
n-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitro-
phenyl)sulfonyl)benzamide;
4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-1-yl)methyl)
piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino-
)-3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclooct-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H--
indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfony-
l)benzamide;
4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-
-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfon-
yl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-
-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfon-
yl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H--
indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfony-
l)benzamide;
4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)p-
iperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)--
3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-
-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfon-
yl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-phe-
noxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(dim-
ethylamino)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morp-
holin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(dim-
ethylamino)butyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((1-(phenylsulfonyl)piperidin-4-yl)amino)phenyl)sulfonyl)-2-phenoxybenzami-
de;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-
-4-((1-(quinolin-8-ylsulfonyl)piperidin-4-yl)amino)phenyl)sulfonyl)-2-phen-
oxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((-
4-((1-(phenylsulfonyl)piperidin-4-yl)amino)-3-((trifluoromethyl)sulfonyl)p-
henyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-(4-
-((1-(quinolin-8-ylsulfonyl)piperidin-4-yl)amino)-3-((trifluoromethyl)sulf-
onyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(((1S)-3-
-(dimethylamino)-1-thien-2-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-pheno-
xybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((thien-2-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((-
4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phe-
nyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((2-(1H-1,2,3-triazol-1-yl)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide-
;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-
-((2-(2H-1,2,3-triazol-2-yl)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamid-
e;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(d-
imethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-naphthyloxy)benzam-
ide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitr-
o-4-((2-(2-oxopyridin-1(2H)-yl)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenza-
mide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nit-
ro-4-((2-(pyridin-2-yloxy)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((2-pyridin-4-ylethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-((trifluoromethyl)sulfonyl-
)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-(trifluoromethyl)phenyl)su-
lfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((3-cyano-4-((3-(dimethylamino)propyl)amino)phenyl)sulfonyl)-2-(1-
H-indol-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yl
oxy)-N-((3-nitro-4-((1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino)pheny-
l)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((4-methylpiperazin-1-yl)amino)-3-nitrop-
henyl)sulfonyl)benzamide;
4-(4-(1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl)piperazin-1-yl)-2-(1H-indol-4-
-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfon-
yl)benzamide;
N-((4-(((4-aminotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulf-
onyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)pipe-
razin-1-yl)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-ylmethyl)a-
mino]phenyl}sulfonyl)benzamide;
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino-
]-3-nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-piperazi-
n-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}s-
ulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylm-
ethyl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylm-
ethyl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4--
ylmethyl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-
-3-nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-
-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;
N-[(4-{[(3S,4R)-1-benzyl-3-hydroxypiperidin-4-yl]amino}-3-nitrophenyl)sul-
fonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(l 1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino-
}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrop-
henyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino-
}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulf-
onyl]-2-(1H-indol-4-yloxy)benzamide;
4-[4-({4'-chloro-3-[3-(dimethylamino)propyl]-1,1'-biphenyl-2-yl}methyl)pi-
perazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-y-
lmethyl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulf-
onyl]-2-(1H-indol-5-yloxy)benzamide;
4-{4-[(4'-chloro-4-morpholin-4-yl-1,1'-biphenyl-2-yl)methyl]piperazin-1-y-
l}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)ami-
no]phenyl}sulfonyl)benzamide;
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pi-
perazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-
-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]--
2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-ni-
trophenyl}sulfonyl)benzamide;
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pi-
perazin-1-yl]-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide;
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-
-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benza-
mide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-{[4-({[4-(dimethylamino)tetrahydro-2H-pyran-4-yl]methyl}amin-
o)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;
N-({4-[(2-aminocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlo-
rophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indo-
l-5-yloxy)benzamide;
4-[4-({4'-chloro-4-[3-(dimethylamino)prop-1-ynyl]-1,1'-biphenyl-2-yl}meth-
yl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyra-
n-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperi-
din-4-yl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[2-(4-hydroxy-1-methylpiperidin-4-yl)ethyl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-yl)piperidin--
4-yl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[4'-chloro-4-(2-hydroxyethoxy)-1,1'-biphenyl-2-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)-
amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)su-
lfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trif-
luoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperi-
din-4-yl]amino}phenyl)sulfonyl]benzamide;
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-
-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benza-
mide;
4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(-
hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperid-
in-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;
4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydro-
xymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-
-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trif-
luoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[4'-chloro-4-(2-hydroxyethoxy)-1,1'-biphenyl-2-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]-
amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]-
amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1--
yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophen-
yl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1--
yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperid-
in-4-yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1--
yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophen-
yl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitrop-
henyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitrop-
henyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-morpholin-4-ylcyclohexyl)methyl]ami-
no}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-ylmethyl)pipe-
ridin-4-yl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-4-ylmethyl)pipe-
ridin-4-yl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3--
nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(2-hydroxyethyl)piperazin-1-yl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3--
nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(3-fluoropropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-indol-5-yloxy)benzamide;
4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydro-
xymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2-
H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(-
hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(1-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]--
2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}su-
lfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2-hydroxy-1-tetrahydro-2H-pyran-4-ylethyl)amino]-3-nitrophe-
nyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-({1-[2-(1H-pyrazol-1-yl)ethyl]pi-
peridin-4-yl}amino)phenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl-
)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfonyl}ben-
zamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfo-
nyl}benzamide;
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-
-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benza-
mide;
4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmeth-
yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-5-morpholin-4-ylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylme-
thyl)amino]phenyl}sulfonyl)benzamide;
N-[(4-{[(1-aminocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-
-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2--
(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxopyrrolidin-1-yl)ethyl]-
amino}phenyl)sulfonyl]benzamide;
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-5-
-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfon-
yl)benzamide;
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazi-
n-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethy-
l)amino]phenyl}sulfonyl)benzamide;
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazi-
n-1-yl)-2-(H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrop-
henyl}sulfonyl)benzamide;
4-{4-[(1R)-1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-in-
dol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)benzamide;
4-{4-[(1S)-1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-in-
dol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)benzamide;
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazi-
n-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitro-
phenyl}sulfonyl)benzamide;
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazi-
n-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpip-
eridin-4-yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-
-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulf-
onyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-3-ylmethyl-
)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulf-
onyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)p-
henyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3-methyloxetan-3-yl)methyl]amino}-3-n-
itrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methoxycyclohexyl)amino]-3-nitrophen-
yl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[3-(1,1-dioxidothiomorpholin-4-yl)propyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxopiperidin-1-yl)ethyl]a-
mino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxoimidazolidin-1-yl)ethy-
l]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-pyridin-4-ylethyl)amino]phen-
yl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-morpholin-4-yl-3-nitrophenyl)sulfonyl]be-
nzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}p-
iperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(4-methoxypiperidin-1-yl)-3-nitr-
ophenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-5-pyrrolidin-1-ylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylm-
ethyl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]a-
mino}phenyl)sulfonyl]benzamide;
4-[4-({4'-chloro-4-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pi-
perazin-1-yl]-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-3-nitrophenyl}sulfon-
yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]--
3-(trifluoromethyl)phenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[2-(1,3-dioxolan-2-yl)ethyl]-3-nitrophenyl}sulfonyl)-2-(1H-in-
dol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy-
)phenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]a-
mino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methyl-5-oxopyrrolidin-3-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methyl-6-oxopiperidin-3-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulf-
onyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulf-
onyl}benzamide;
4-(4-{[4-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl]methyl}piperazin-1-yl)-
-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino-
]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methyloxetan-3-yl)methoxy]-3-nitroph-
enyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1-oxidotetrahydro-2H-thiopyra-
n-4-yl)methyl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1,3-thiazol-5-ylmethyl)amino]p-
henyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy-
)phenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl-
)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-tetrahydro-2H-pyran-4-ylethy-
l)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amin-
o}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitr-
ophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[3-(methylsulfonyl)propyl]amino}-3-nitr-
ophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[3-(1,1-dioxidothiomorpholin-4-yl)propyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethyl-
)phenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indol--
5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitr-
ophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-3-nitrophenyl}sulfon-
yl)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amin-
o}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}-3-ni-
trophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2,2-difluoroethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indo-
l-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]--
3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]--
3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4,4-difluorocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-
-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sul-
fonyl)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[4-(4-chlorophenyl)-1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl]methy-
l}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]-
carbonyl}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromet-
hyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]--
2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-n-
itrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]--
2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-n-
itrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethox-
y)phenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromet-
hyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[3-(methylsulfonyl)propoxy]-3-nitropheny-
l}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}s-
ulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(H-indol-4-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}su-
lfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-y-
loxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-y-
loxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[(3R)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sul-
fonyl}-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[Cis-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulf-
onyl}-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]ph-
enyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]ph-
enyl}sulfonyl)benzamide;
N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfony-
l)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sul-
fonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-(methylamino)-3-[(trifluoromethyl)sulfon-
yl]phenyl}sulfonyl)benzamide;
N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(-
4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-y-
l)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[4-(4-chlorophenyl)-6-isopropoxypyridin-3-yl]methyl}piperazin-1-yl)-
-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino-
]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(l
1H-indol-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(1,3-thiazol--
2-yl)pyridin-3-yl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(2-methoxyethyl)amino]carbonyl}phenyl)-
sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfony-
l}-2-(1H-indol-5-yloxy)benzamide;
N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-
-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino-
}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H--
indol-5-yloxy)benzamide;
N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-
-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino-
}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[4'-chloro-5-(trifluoromethyl)-1,1'-biphenyl-2-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)-
amino]phenyl}sulfonyl)benzamide;
4-(4-{[4'-chloro-5-(trifluoromethyl)-1,1'-biphenyl-2-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)-
phenyl]sulfonyl}benzamide;
4-{4-[(5-tert-butyl-4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-
-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]p-
henyl}sulfonyl)benzamide;
4-{4-[(5-tert-butyl-4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-
-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-
sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phe-
nyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phe-
nyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]-
carbonyl}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-i-
ndol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-i-
ndol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trif-
luoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trif-
luoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfony-
l)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-2-(l 1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(H-indol-5-yloxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-[(triflu-
oromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}s-
ulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)oxy]-3-nitrophe-
nyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitr-
ophenyl}sulfonyl)benzamide;
4-(4-{[4-(4-chlorophenyl)-1-(3-hydroxypropyl)-1,2,5,6-tetrahydropyridin-3-
-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-
-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; benzyl
4-({[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl-
}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenyl-
]amino}methyl)piperidine-1-carboxylate;
N-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-
-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[4'-chloro-5-(trifluoromethyl)-1,1'-biphenyl-2-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiper-
idin-4-yl)amino]phenyl}sulfonyl)benzamide;
4-{4-[(5-tert-butyl-4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-
-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4--
yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-methyl-1H-imidazol-5-yl)methyl]amin-
o}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylsulfonyl)phenyl]sulfonyl}-
benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl-
}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitropheny-
l}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-ni-
trophenyl}sulfonyl)benzamide;
N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(-
4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-y-
l)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-{[6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]--
5-(1,3-thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(3,3-dimethylbutyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indo-
l-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(S)-1-(hydroxymethyl)-3-methylbutyl]amino}-3-nitrophenyl)su-
lfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(2R)-tetrahydrofuran-2-ylmethy-
l]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(1R)-1-(hydroxymethyl)-2-methylpropyl]amino}-3-nitrophenyl)-
sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methoxyphenyl)amino]-3-nitrophenyl}s-
ulfonyl)benzamide;
N-[(4-{[2-(1,3-benzodioxol-5-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-
-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl-
)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(2-oxopyrrolidin-1-yl)propyl-
]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-hydroxyphenyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol--
5-yloxy)benzamide;
N-{[4-({2-[4-(aminosulfonyl)phenyl]ethyl}amino)-3-nitrophenyl]sulfonyl}-4-
-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
-yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[3-(1H-imidazol-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1S)-1-phenylethyl]amino}pheny-
l)sulfonyl]benzamide;
N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sul-
fonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitro-
phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitro-
phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylsulfonyl)phenyl]sulfonyl}benzamid-
e;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(methylsulfonyl)phenyl]sulfonyl}benzam-
ide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitroph-
enyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3--
yl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfony-
l}-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfon-
yl}-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H--
indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpipe-
ridin-4-yl)oxy]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitr-
ophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfo-
nyl}-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H--
indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3--
yl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(3-hydroxy-4-methoxyphenyl)amino]-3-nitrophenyl}sulfonyl)-2--
(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2,3-dihydro-1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)ami-
no]-3-nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(py-
ridin-3-ylamino)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phen-
yl}sulfonyl)-2-(pyridin-3-ylamino)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phen-
yl}sulfonyl)-2-(pyridin-3-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1,2,3,4-tetrahydroisoquinolin-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indazol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmeth-
yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indazol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpi-
peridin-4-yl)amino]phenyl}sulfonyl)benzamide;
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-indazol-4-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)ami-
no]-3-nitrophenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-y-
lmethyl)amino]phenyl}sulfonyl)benzamide;
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}su-
lfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}su-
lfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3--
yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrro-
lidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-y-
l)methoxy]-3-nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethy-
l)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)su-
lfonyl]-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfony-
l]-2-(1H-indazol-4-yloxy)benzamide;
N-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3-
-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
Trans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-
-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin-
-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-
-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-
-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide;
N-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-
-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-chloro-6-(tetrahydrofuran-3-ylmethoxy)pyridin-3-yl]sulfonyl}--
2-(1H-indazol-4-yloxy)benzamide;
Trans-N-({5-chloro-6-[(4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-
-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3--
yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)m-
orpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-
-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)m-
orpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-
-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridi-
n-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]-
methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridi-
n-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]-
methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfon-
yl}-2-(1H-indazol-4-yloxy)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin--
3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethy-
l]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrr-
olidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]-
methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)me-
thyl]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-oxetan-3-ylmorpholin-
-2-yl)methyl]amino}phenyl)sulfonyl]benzamide;
N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}o-
xy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-
-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amin-
o)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-(1H-indazol-4-yloxy)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)mor-
pholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)mor-
pholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmet-
hyl)amino]phenyl}sulfonyl)benzamide;
Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)meth-
yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4--
yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H--
pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran--
4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}m-
ethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridi-
n-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]-
methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-indazol-4-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]am-
ino}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indazo-
l-4-yloxy)benzamide;
N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-
-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)-
amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3--
nitrophenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)ami-
no]-3-nitrophenyl}sulfonyl)benzamide;
Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexy-
l)amino]-3-nitrophenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]-
amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({(2R)-4-[2-(2-methoxyethoxy)eth-
yl]morpholin-2-yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]-
amino}-3-nitrophenyl)sulfonyl]benzamide;
N-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(-
1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1--
en-1-yl]methyl}piperazin-1-yl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2--
yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[6-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}m-
ethoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)be-
nzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}p-
iperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl-
}sulfonyl)-2-phenoxybenzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-chloro-6-(2-tetrahydrofuran-2-ylethoxy)pyridin-3-yl]sulfonyl}-
-2-(1H-indazol-4-yloxy)benzamide;
Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyanocyclohexyl)methyl-
]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4,4-difluorocyclohexyl)metho-
xy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-
-en-1-yl]methyl}piperazin-1-yl)benzamide;
N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl-
)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}su-
lfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]m-
ethyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-cyano-6-(2-tetrahydro-2H-pyran-4-ylethoxy)pyridin-3-yl]sulfon-
yl}-2-(H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oc-
t-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-p-
henoxy-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.-
1]hept-3-yl]amino}piperidin-1-yl)benzamide;
N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxy-4-
-(4-{(3-phenylpropanoyl)
[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-y-
l)benzamide;
N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-p-
henoxy-4-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]h-
ept-3-yl]amino}piperidin-1-yl)benzamide;
N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxy-4-
-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl-
]amino}piperidin-1-yl)benzamide;
4-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)piper-
azin-1-yl]-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-
-phenoxybenzamide;
4-[4-(2-({[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)pipe-
razin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}su-
lfonyl)-2-phenoxybenzamide;
4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-N-({3-nitro-4-
-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamid-
e;
4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-2-phenoxy-N-
-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]-
phenyl}sulfonyl)benzamide;
4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-2-phenoxy-N-(-
{4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-N-({4-[(3-mor-
pholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide;
4-(4-{2-[(4R,7S)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoinden-5-yl]benzyl}-
piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pheny-
l}sulfonyl)-2-phenoxybenzamide;
4-[4-(2-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzyl)p-
iperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl-
}sulfonyl)-2-phenoxybenzamide;
4-[4-(2-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzylid-
ene)piperidin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]p-
henyl}sulfonyl)-2-phenoxybenzamide;
4-[4-(3-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzyl)p-
iperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl-
}sulfonyl)-2-phenoxybenzamide; and therapeutically acceptable
salts, prodrugs, salts of prodrugs and metabolites thereof.
In another aspect, the present invention provides compounds of
Formula (II)
##STR00010## and therapeutically acceptable salts, prodrugs, salts
of prodrugs and metabolites thereof, wherein A.sup.1, B.sup.1,
D.sup.1, E.sup.1, Y.sup.1, R.sup.30, and R.sup.37 are as described
herein for Formula (I), n is 0, 1, 2, or 3; describing the number
of substituents on R.sup.26, and R.sup.100 is as described for
substituents on R.sup.26.
In one embodiment of Formula (II), A.sup.1 is N. In another
embodiment of Formula (II), A.sup.1 is C(A.sup.2). In another
embodiment of Formula (II), A.sup.1 is C(A.sup.2), and A.sup.2 is
H.
In one embodiment of Formula (II), B.sup.1 is R.sup.1, OR.sup.1,
SR.sup.1, SO.sub.2R.sup.1, NHR.sup.1, N(R.sup.1).sub.2, or
C(O)NHR.sup.1. In another embodiment of Formula (II), B.sup.1 is
NHR.sup.1. In another embodiment of Formula (II), B.sup.1 is
NHR.sup.1, and A.sup.1 is C(A.sup.2), and A.sup.2 is H. In another
embodiment of Formula (II), B.sup.1 is OR.sup.1. In another
embodiment of Formula (II), B.sup.1 is OR.sup.1, and A.sup.1 is
C(A.sup.2), and A.sup.2 is H.
In one embodiment of Formula (II), D.sup.1 and E.sup.1 are H. In
another embodiment of Formula (II), B.sup.1 is NHR.sup.1, and
A.sup.1 is C(A.sup.2), A.sup.2 is H, and D.sup.1 and E.sup.1 are H.
In another embodiment of Formula (II), B.sup.1 is OR.sup.1, and
A.sup.1 is C(A.sup.2), A.sup.2 is H, and D.sup.1 and E.sup.1 are
H.
In one embodiment of Formula (II), Y.sup.1 is H, CN, NO.sub.2, F,
Cl, Br, I, CF.sub.3, R.sup.17, NHC(O)R.sup.17, or C(O)NH.sub.2. In
another embodiment of Formula (II), Y.sup.1 is NO.sub.2. In another
embodiment of Formula (I), B.sup.1 is NHR.sup.1, and A.sup.1 is
C(A.sup.2), A.sup.2 is H, D.sup.1 and E.sup.1 are H, and Y.sup.1 is
NO.sub.2. In another embodiment of Formula (II), Y.sup.1 is Cl. In
another embodiment of Formula (II), B.sup.1 is OR.sup.1, and
A.sup.1 is C(A.sup.2), A.sup.2 is H, D.sup.1 and E.sup.1 are H, and
Y.sup.1 is Cl.
In one embodiment of Formula (II), R.sup.1 is R.sup.2, R.sup.3,
R.sup.4 or R.sup.5. In another embodiment of Formula (II), R.sup.1
is R.sup.2, and R.sup.2 is phenyl.
In one embodiment of Formula (II), R.sup.1 is R.sup.3, and R.sup.3
is heteroaryl. In another embodiment of Formula (II), R.sup.3 is
triazolyl.
In one embodiment of Formula (II), R.sup.1 is R.sup.4. In another
embodiment of Formula (II), R.sup.1 is R.sup.4, and R.sup.4 is
cycloalkyl. In another embodiment of Formula (II), R.sup.1 is
R.sup.4, and R.sup.4 is cyclohexyl. In another embodiment of
Formula (II), R.sup.1 is R.sup.4, and R.sup.4 is heterocycloalkyl.
In another embodiment of Formula (II), R.sup.1 is R.sup.4, and
R.sup.4 is 8-azabicyclo[3.2.1]octane, azetidinyl, piperidinyl,
piperazinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, or
tetrahydrothiophenyl. In another embodiment of Formula (II),
R.sup.1 is R.sup.4, and R.sup.4 is heterocycloalkenyl. In another
embodiment of Formula (II), R.sup.1 is R.sup.4, and R.sup.4 is
tetrahydropyridazinyl.
In one embodiment of Formula (II), R.sup.1 is R.sup.5. In another
embodiment of Formula (II), R.sup.1 is R.sup.5 and R.sup.5 is alkyl
or alkynyl. In another embodiment of Formula (II), R.sup.1 is
R.sup.5 and R.sup.5 is alkyl which is unsubstituted. In another
embodiment of Formula (II), R.sup.1 is R.sup.5 and R.sup.5 is alkyl
which is substituted with one or two or three independently
selected R.sup.6, R.sup.7, OR.sup.7, SR.sup.7, SO.sub.2R.sup.7,
N(R.sup.7).sub.2, OH, CN, CF.sub.3, F, Cl, Br or I substituents. In
another embodiment of Formula (II), R.sup.1 is R.sup.5 and R.sup.5
is alkyl which is substituted with R.sup.7.
In one embodiment of Formula (II), R.sup.7 is R.sup.8, R.sup.9,
R.sup.10 or R.sup.11. In another embodiment of Formula (II),
R.sup.7 is R.sup.8, and R.sup.8 is phenyl which is unfused or fused
with R.sup.8A, and R.sup.8A is heterocycloalkane. In another
embodiment of Formula (II), R.sup.7 is R.sup.8, and R.sup.8 is
phenyl which is unfused. In another embodiment of Formula (II),
R.sup.7 is R.sup.9, and R.sup.9 is heteroaryl. In another
embodiment of Formula (II), R.sup.7 is R.sup.9, and R.sup.9 is
furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,
1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,
pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl,
thiophenyl, triazinyl or 1,2,3-triazolyl. In another embodiment of
Formula (II), R.sup.1 is R.sup.9, and R.sup.9 is pyridinyl,
thiazolyl, imidazoyl, and 1,2,3-triazolyl. In another embodiment of
Formula (II), R.sup.7 is R.sup.10, and R.sup.10 is
C.sub.3-C.sub.10-cycloalkyl. In another embodiment of Formula (II),
R.sup.7 is R.sup.10, and R.sup.10 is C.sub.6 or
C.sub.10-cycloalkyl. In another embodiment of Formula (II), R.sup.7
is R.sup.10, and R.sup.10 is cyclohexyl or adamantanyl. In another
embodiment of Formula (II), R.sup.7 is R.sup.10, and R.sup.10 is
morpholinyl, piperazinyl, piperidinyl, tetrahydro-2H-pyranyl,
1,2-dihydropyridinyl, pyranyl, pyridin-1(H)-yl, pyrrolidinyl,
oxetanyl, thiomorpholinyl, imidazolidinyl, tetrahydrothiophenyl,
dioxolanyl, tetrahydrothiopyranyl, dioxanyl, or tetrahydrofuranyl.
In another embodiment of Formula (II), R.sup.7 is R.sup.10, and
R.sup.10 is morpholinyl, piperazinyl, piperidinyl,
tetrahydro-2H-pyranyl, 1,2-dihydropyridinyl, pyrrolidinyl,
oxetanyl, thiomorpholinyl, imidazolidinyl, tetrahydrothiophenyl,
dioxolanyl, tetrahydrothiopyranyl, dioxanyl, or tetrahydrofuranyl.
In another embodiment of Formula (II), R.sup.7 is R.sup.11, and
R.sup.11 is alkyl which is unsubstituted or substituted. In another
embodiment of Formula (II), R.sup.7 is R.sup.1, and R.sup.11 is
alkyl which is unsubstituted. In another embodiment of Formula
(II), R.sup.7 is R.sup.11, and R.sup.11 is alkyl which is
substituted. In another embodiment of Formula (II), R.sup.7 is
R.sup.11, and R.sup.11 is alkyl which is substituted with one or
two or three independently selected OR.sup.12, F, Cl, Br or I
substituents. In another embodiment of Formula (II), R.sup.7 is
R.sup.11, R.sup.11 is alkyl which is substituted with OR.sup.12,
R.sup.1 is R.sup.16, and R.sup.16 is alkyl.
In one embodiment of Formula (II), R.sup.17 is R.sup.19 or
R.sup.21. In another embodiment of Formula (II), R.sup.17 is
R.sup.19, and R.sup.19 is heteroaryl. In another embodiment of
Formula (II), R.sup.17 is R.sup.19, and R.sup.19 is thiazolyl. In
another embodiment of Formula (II), R.sup.17 is R.sup.21, and
R.sup.21 is alkynyl. In another embodiment of Formula (II),
R.sup.17 is R.sup.21, and R.sup.21 is ethynyl.
Still another embodiment pertains to compounds having Formula II
which are
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piper-
azin-1-yl)-N-((4-((1-cyclopentylpiperidin-4-yl)amino)-3-nitrophenyl)sulfon-
yl)-2-(1H-indol-5-yloxy)benzamide
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5--
yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfony-
l)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benza-
mide;
4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)pipe-
razin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-n-
itrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1-
H-indol-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrop-
henyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1-
H-indol-5-yloxy)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5--
yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzam-
ide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indo-
l-5-yloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluorometh-
yl)sulfonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-2-(-
1H-indol-5-yloxy)benzamide;
N-((3-((chloro(difluoro)methyl)sulfonyl)-4-((3-(dimethylamino)propyl)amin-
o)phenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-y-
l)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;
N-((3-((chloro(difluoro)methyl)sulfonyl)-4-((1-methylpiperidin-4-yl)amino-
)phenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl-
)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H--
indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfony-
l)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-((trif-
luoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-
-3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-(4-methylpiperazin-1-yl)propyl)amino-
)-3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)-
phenyl)sulfonyl)benzamide
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrop-
henyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-(3-(dimethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-(1H-indo-
l-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2
(1H-indol-5-yloxy)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)--
3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-(4-methylpiperazin-1-yl)-3-nitrophenyl)s-
ulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-(((4-(dimethylamino)-1-methylpiperidin-4-yl)methyl)amino)-3-n-
itrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-y-
lmethyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl-
methyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-y-
lmethyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-3-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl-
methyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl-
)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl-
)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)-
amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydro-
-1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)ph-
enyl)sulfonyl)benzamide;
4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)p-
iperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)--
3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(H--
indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfony-
l)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-((trifluoromethyl)sulfonyl-
)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-(trifluoromethyl)phenyl)su-
lfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((3-cyano-4-((3-(dimethylamino)propyl)amino)phenyl)sulfonyl)-2-(1-
H-indol-5-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((1-tetrahydro-2H-pyran-4-ylpipe-
ridin-4-yl)amino)phenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((4-methylpiperazin-1-yl)amino)-3-nitrop-
henyl)sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl-
)amino]phenyl}sulfonyl)benzamide;
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino-
]-3-nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}su-
lfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylm-
ethyl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylm-
ethyl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4--
ylmethyl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-
-3-nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-
-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;
N-[(4-{[(3S,4R)-1-benzyl-3-hydroxypiperidin-4-yl]amino}-3-nitrophenyl)sul-
fonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino-
}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-5-fluoro-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-
-3-nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-5-fluoro-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-
-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulf-
onyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[4-(dimethylamino)tetrahydro-2H-pyran-4-yl]methyl}amino)-3--
nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;
N-({4-[(2-aminocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlo-
rophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indo-
l-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[2-(4-hydroxy-1-methylpiperidin-4-yl)ethyl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-yl)piperidin--
4-yl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)su-
lfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperi-
din-4-yl]amino}phenyl)sulfonyl]benzamide;
4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydro-
xymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4--
yl)amino]-3-nitrophenyl}sulfonyl)benzamide;
4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydro-
xymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-
-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trif-
luoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]-
amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1--
yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophen-
yl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1--
yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperid-
in-4-yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1--
yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophen-
yl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitrop-
henyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-morpholin-4-ylcyclohexyl)methyl]ami-
no}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-ylmethyl)pipe-
ridin-4-yl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-4-ylmethyl)pipe-
ridin-4-yl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3--
nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(2-hydroxyethyl)piperazin-1-yl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3--
nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(3-fluoropropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-indol-5-yloxy)benzamide;
4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydro-
xymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2-
H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(-
hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(1-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]--
2-(H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2-hydroxy-1-tetrahydro-2H-pyran-4-ylethyl)amino]-3-nitrophe-
nyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-({1-[2-(1H-pyrazol-1-yl)ethyl]pi-
peridin-4-yl}amino)phenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfonyl}ben-
zamide;
4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylme-
thyl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-5-morpholin-4-ylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylme-
thyl)amino]phenyl}sulfonyl)benzamide;
N-[(4-{[(1-aminocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-
-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2--
(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxopyrrolidin-1-yl)ethyl]-
amino}phenyl)sulfonyl]benzamide;
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-5-
-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfon-
yl)benzamide;
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazi-
n-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethy-
l)amino]phenyl}sulfonyl)benzamide;
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazi-
n-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitro-
phenyl}sulfonyl)benzamide;
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazi-
n-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitro-
phenyl}sulfonyl)benzamide;
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazi-
n-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpip-
eridin-4-yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-
-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulf-
onyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-3-ylmethyl-
)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)p-
henyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3-methyloxetan-3-yl)methyl]amino}-3-n-
itrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methoxycyclohexyl)amino]-3-nitrophen-
yl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[3-(1,1-dioxidothiomorpholin-4-yl)propyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxopiperidin-1-yl)ethyl]a-
mino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxoimidazolidin-1-yl)ethy-
l]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-pyridin-4-ylethyl)amino]phen-
yl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-morpholin-4-yl-3-nitrophenyl)sulfonyl]be-
nzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}p-
iperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(4-methoxypiperidin-1-yl)-3-nitr-
ophenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-5-pyrrolidin-1-ylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylm-
ethyl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]a-
mino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-3-nitrophenyl}sulfon-
yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]--
3-(trifluoromethyl)phenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[2-(1,3-dioxolan-2-yl)ethyl]-3-nitrophenyl}sulfonyl)-2-(1H-in-
dol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy-
)phenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(l
1H-indol-5-yloxy)-N-({4-[(1-methyl-5-oxopyrrolidin-3-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methyl-6-oxopiperidin-3-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulf-
onyl}benzamide;
4-(4-{[4-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl]methyl}piperazin-1-yl)-
-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino-
]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methyloxetan-3-yl)methoxy]-3-nitroph-
enyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1-oxidotetrahydro-2H-thiopyra-
n-4-yl)methyl]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1,3-thiazol-5-ylmethyl)amino]p-
henyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl-
)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-tetrahydro-2H-pyran-4-ylethy-
l)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethyl-
)phenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indol--
5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitr-
ophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amin-
o}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2,2-difluoroethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indo-
l-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]--
3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4,4-difluorocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-
-indol-5-yloxy)benzamide;
4-(4-{[4-(4-chlorophenyl)-1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl]methy-
l}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]-
carbonyl}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]--
2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-n-
itrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]--
2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-n-
itrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromet-
hyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}s-
ulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-y-
loxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[(3R)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sul-
fonyl}-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({[(3R)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sul-
fonyl}-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]ph-
enyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sul-
fonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-(methylamino)-3-[(trifluoromethyl)sulfon-
yl]phenyl}sulfonyl)benzamide;
N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(-
4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-y-
l)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[4-(4-chlorophenyl)-6-isopropoxypyridin-3-yl]methyl}piperazin-1-yl)-
-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino-
]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(1,3-
-thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(H-indol-5-yloxy)-N-[(4-{[(2-methoxyethyl)amino]carbonyl}phenyl)s-
ulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfony-
l}-2-(1H-indol-5-yloxy)benzamide;
N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-
-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino-
}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H--
indol-5-yloxy)benzamide;
4-(4-{[4'-chloro-5-(trifluoromethyl)-1,1'-biphenyl-2-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)-
amino]phenyl}sulfonyl)benzamide;
4-(4-{[4'-chloro-5-(trifluoromethyl)-1,1'-biphenyl-2-yl]methyl}piperazin--
1-yl)-2-(l
1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethox-
y)phenyl]sulfonyl}benzamide;
4-{4-[(5-tert-butyl-4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-
-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]p-
henyl}sulfonyl)benzamide;
4-{4-[(5-tert-butyl-4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-
-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-
sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phe-
nyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]-
carbonyl}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-i-
ndol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-i-
ndol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trif-
luoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfony-
l)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-[(trifl-
uoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}s-
ulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)oxy]-3-nitrophe-
nyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitr-
ophenyl}sulfonyl)benzamide; benzyl
4-({[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl-
}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenyl-
]amino}methyl)piperidine-1-carboxylate;
N-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-
-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[4'-chloro-5-(trifluoromethyl)-1,1'-biphenyl-2-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiper-
idin-4-yl)amino]phenyl}sulfonyl)benzamide;
4-{4-[(5-tert-butyl-4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-
-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4--
yl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-methyl-1H-imidazol-5-yl)methyl]amin-
o}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylsulfonyl)phenyl]sulfonyl}-
benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl-
}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitropheny-
l}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-ni-
trophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(3,3-dimethylbutyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indo-
l-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(1S)-1-(hydroxymethyl)-3-methylbutyl]amino}-3-nitrophenyl)s-
ulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(2R)-tetrahydrofuran-2-ylmethy-
l]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(1R)-1-(hydroxymethyl)-2-methylpropyl]amino}-3-nitrophenyl)-
sulfonyl]-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methoxyphenyl)amino]-3-nitrophenyl}s-
ulfonyl)benzamide;
N-[(4-{[2-(1,3-benzodioxol-5-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-
-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl-
)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(2-oxopyrrolidin-1-yl)propyl-
]amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-hydroxyphenyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol--
5-yloxy)benzamide;
N-{[4-({2-[4-(aminosulfonyl)phenyl]ethyl}amino)-3-nitrophenyl]sulfonyl}-4-
-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
-yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[3-(1H-imidazol-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1S)-1-phenylethyl]amino}pheny-
l)sulfonyl]benzamide;
N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sul-
fonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitro-
phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylsulfonyl)phenyl]sulfonyl}benzamid-
e;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophen-
yl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3--
yl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H--
indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpipe-
ridin-4-yl)oxy]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitr-
ophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(3-hydroxy-4-methoxyphenyl)amino]-3-nitrophenyl}sulfonyl)-2--
(1H-indol-5-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oc-
t-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide; and therapeutically
acceptable salts, prodrugs, salts of prodrugs and metabolites
thereof.
In another aspect, the present invention provides compounds of
Formula (III)
##STR00011## and therapeutically acceptable salts, prodrugs, salts
of prodrugs and metabolites thereof, wherein A.sup.1, B.sup.1,
D.sup.1, E.sup.1, Y.sup.1, R.sup.30, and R.sup.37 are as described
herein for Formula (I), n is 0, 1, 2, or 3; describing the number
of substituents on R.sup.26, and R.sup.100 is as described for
substituents on R.sup.26.
In one embodiment of Formula (III), A.sup.1 is N. In another
embodiment of Formula (III), A.sup.1 is C(A.sup.2). In another
embodiment of Formula (III), A.sup.1 is C(A.sup.2), and A.sup.2 is
H.
In one embodiment of Formula (III), B.sup.1 is R.sup.1, OR.sup.1,
SR.sup.1, SO.sub.2R.sup.1, NHR.sup.1, N(R.sup.1).sub.2, or
C(O)NHR.sup.1. In another embodiment of Formula (III), B.sup.1 is
NHR.sup.1. In another embodiment of Formula (I), B.sup.1 is
NHR.sup.1, and A.sup.1 is C(A.sup.2), and A.sup.2 is H. In another
embodiment of Formula (III), B.sup.1 is OR.sup.1. In another
embodiment of Formula (III), B.sup.1 is OR.sup.1, and A.sup.1 is
C(A.sup.2), and A.sup.2 is H.
In one embodiment of Formula (III), D.sup.1 and E.sup.1 are H. In
another embodiment of Formula (III), B.sup.1 is NHR.sup.1, and
A.sup.1 is C(A.sup.2), A.sup.2 is H, and D.sup.1 and E.sup.1 are H.
In another embodiment of Formula (III), B.sup.1 is OR.sup.1, and
A.sup.1 is C(A.sup.2), A.sup.2 is H, and D.sup.1 and E.sup.1 are
H.
In one embodiment of Formula (III), Y is H, CN, NO.sub.2, F, Cl,
Br, I, CF.sub.3, R.sup.17, NHC(O)R.sup.17, or C(O)NH.sub.2. In
another embodiment of Formula (III), Y.sup.1 is NO.sub.2. In
another embodiment of Formula (III), B.sup.1 is NHR.sup.1, and
A.sup.1 is C(A.sup.2), A.sup.2 is H, D.sup.1 and E.sup.1 are H, and
Y.sup.1 is NO.sub.2. In another embodiment of Formula (III), YL is
Cl. In another embodiment of Formula (III), B.sup.1 is OR.sup.1,
and A.sup.1 is C(A.sup.2), A.sup.2 is H, D.sup.1 and E.sup.1 are H,
and Y.sup.1 is Cl.
In one embodiment of Formula (III), R.sup.1 is R.sup.2, R.sup.3,
R.sup.4 or R.sup.5. In another embodiment of Formula (III), R.sup.1
is R.sup.2, and R.sup.2 is phenyl.
In one embodiment of Formula (III), R.sup.1 is R.sup.3, and R.sup.3
is heteroaryl. In another embodiment of Formula (III), R.sup.3 is
triazolyl.
In one embodiment of Formula (III), R.sup.1 is R.sup.4. In another
embodiment of Formula (III), R.sup.1 is R.sup.4, and R.sup.4 is
cycloalkyl. In another embodiment of Formula (III), R.sup.1 is
R.sup.4, and R.sup.4 is cyclohexyl. In another embodiment of
Formula (III), R.sup.1 is R.sup.4, and R.sup.4 is
heterocycloalkyl.
In another embodiment of Formula (III), R.sup.1 is R.sup.4, and
R.sup.4 is 8-azabicyclo[3.2.1]octane, azetidinyl, piperidinyl,
piperazinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, or
tetrahydrothiophenyl. In another embodiment of Formula (III),
R.sup.1 is R.sup.4, and R.sup.4 is heterocycloalkenyl. In another
embodiment of Formula (III), R.sup.1 is R.sup.4, and R.sup.4 is
tetrahydropyridazinyl.
In one embodiment of Formula (III), R.sup.1 is R.sup.5. In another
embodiment of Formula (III), R.sup.1 is R.sup.5 and R.sup.5 is
alkyl or alkynyl. In another embodiment of Formula (III), R.sup.1
is R.sup.5 and R.sup.5 is alkyl which is unsubstituted. In another
embodiment of Formula (III), R.sup.1 is R.sup.5 and R.sup.5 is
alkyl which is substituted with one or two or three independently
selected R.sup.6, R.sup.7, OR.sup.7, SR.sup.7, SO.sub.2R.sup.7,
N(R.sup.7).sub.2, OH, CN, CF.sub.3, F, Cl, Br or I substituents. In
another embodiment of Formula (III), R.sup.1 is R.sup.5 and R.sup.5
is alkyl which is substituted with R.sup.7.
In one embodiment of Formula (III), R.sup.7 is R.sup.8, R.sup.9,
R.sup.10 or R.sup.11. In another embodiment of Formula (III),
R.sup.7 is R.sup.8, and R.sup.8 is phenyl which is unfused or fused
with R.sup.8A, and R.sup.8A is heterocycloalkane. In another
embodiment of Formula (III), R.sup.7 is R.sup.8, and R.sup.8 is
phenyl which is unfused. In another embodiment of Formula (III),
R.sup.7 is R.sup.9, and R.sup.9 is heteroaryl. In another
embodiment of Formula (III), R.sup.7 is R.sup.9, and R.sup.9 is
furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,
1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,
pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl,
thiophenyl, triazinyl or 1,2,3-triazolyl.
In another embodiment of Formula (III), R.sup.7 is R.sup.9, and
R.sup.9 is pyridinyl, thiazolyl, imidazoyl, and 1,2,3-triazolyl. In
another embodiment of Formula (III), R.sup.7 is R.sup.10, and
R.sup.10 is C.sub.3-C.sub.10-cycloalkyl. In another embodiment of
Formula (III), R.sup.7 is R.sup.10, and R.sup.10 is C.sub.6 or
C.sub.10-cycloalkyl. In another embodiment of Formula (III),
R.sup.7 is R.sup.10, and R.sup.10 is cyclohexyl or adamantanyl. In
another embodiment of Formula (III), R.sup.7 is R.sup.10, and
R.sup.10 is morpholinyl, piperazinyl, piperidinyl,
tetrahydro-2H-pyranyl, 1,2-dihydropyridinyl, pyranyl,
pyridin-1(H)-yl, pyrrolidinyl, oxetanyl, thiomorpholinyl,
imidazolidinyl, tetrahydrothiophenyl, dioxolanyl,
tetrahydrothiopyranyl, dioxanyl, or tetrahydrofuranyl. In another
embodiment of Formula (III), R.sup.7 is R.sup.10, and R.sup.10 is
morpholinyl, piperazinyl, piperidinyl, tetrahydro-2H-pyranyl,
1,2-dihydropyridinyl, pyrrolidinyl, oxetanyl, thiomorpholinyl,
imidazolidinyl, tetrahydrothiophenyl, dioxolanyl,
tetrahydrothiopyranyl, dioxanyl, or tetrahydrofuranyl. In another
embodiment of Formula (III), R.sup.7 is R.sup.11, and R.sup.11 is
alkyl which is unsubstituted or substituted. In another embodiment
of Formula (III), R.sup.7 is R.sup.11, and R.sup.11 is alkyl which
is unsubstituted. In another embodiment of Formula (III), R.sup.7
is R.sup.11, and R.sup.11 is alkyl which is substituted. In another
embodiment of Formula (III), R.sup.7 is R.sup.11, and R.sup.11 is
alkyl which is substituted with one or two or three independently
selected OR.sup.12, F, Cl, Br or I substituents. In another
embodiment of Formula (III), R.sup.7 is R.sup.11, R.sup.11 is alkyl
which is substituted with OR.sup.1, R.sup.12 is R.sup.16, and
R.sup.16 is alkyl.
In one embodiment of Formula (III), R.sup.17 is R.sup.19 or
R.sup.21. In another embodiment of Formula (III), R.sup.17 is
R.sup.19, and R.sup.19 is heteroaryl. In another embodiment of
Formula (III), R.sup.17 is R.sup.19, and R.sup.19 is thiazolyl. In
another embodiment of Formula (III), R.sup.17 is R.sup.21, and
R.sup.21 is alkynyl. In another embodiment of Formula (III),
R.sup.17 is R.sup.21, and R.sup.21 is ethynyl.
Still another embodiment pertains to compounds having Formula (III)
which are
4-(4-((4'-chloro-4-(pyrrolidin-1-ylmethyl)-1,1'-biphenyl-2-yl)methyl)-
piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-
-ylmethyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl-
methyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4--
yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfony-
l)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benza-
mide;
4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)pipe-
razin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-n-
itrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrop-
henyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1-
H-indol-4-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1-
H-indol-4-yloxy)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4--
yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzam-
ide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indo-
l-4-yloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluorometh-
yl)sulfonyl)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4--
yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-((trifluoromethyl)sulfonyl)-
phenyl)sulfonyl)benzamide;
2-(1H-indol-4-yloxy)-4-(4-((2-(4-methoxyphenyl)-4,4-dimethylcyclohex-1-en-
-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino-
)phenyl)sulfonyl)benzamide;
4-(4-((4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)cyclohex-1-en-1-yl)methy-
l)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpr-
opyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4,4-dimethyl-2-(4-(trifluoromethoxy)phenyl)cyclohex-1-en-1-yl)meth-
yl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylp-
ropyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4,4-dimethyl-2-(3-(trifluoromethyl)phenyl)cyclohex-1-en-1-yl)methy-
l)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpr-
opyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((2-(3-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)-
phenyl)sulfonyl)benzamide;
4-(4-((2-(4-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)-
phenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-(4-methylpiperazin-1-yl)propyl)amino-
)-3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-
-3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)-
phenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrop-
henyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)--
3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-(3-(dimethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-(1H-indo-
l-4-yloxy)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((1-(2,2,2-trifluoroethyl)piperi-
din-4-yl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-y-
lmethyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)-1,1'-biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-y-
lmethyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl-
methyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((4'-chloro-3-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl-
methyl)amino)phenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-
-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfo-
nyl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclooct-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H--
indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfon-
yl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-
-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfo-
nyl)benzamide;
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en-1-yl)methyl)piperazi-
n-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitro-
phenyl)sulfonyl)benzamide;
4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)p-
iperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)--
3-nitrophenyl)sulfonyl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclooct-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H--
indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfony-
l)benzamide;
4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-
-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfon-
yl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-
-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfon-
yl)benzamide;
4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H--
indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfony-
l)benzamide;
4-(4-(1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl)piperazin-1-yl)-2-(1H-indol-4-
-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfon-
yl)benzamide;
N-((4-(((4-aminotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulf-
onyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)pipe-
razin-1-yl)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrop-
henyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino-
}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulf-
onyl]-2-(1H-indol-4-yloxy)benzamide;
4-[4-({4'-chloro-3-[3-(dimethylamino)propyl]-1,1'-biphenyl-2-yl}methyl)pi-
perazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-y-
lmethyl)amino]phenyl}sulfonyl)benzamide;
4-{4-[(4'-chloro-4-morpholin-4-yl-1,1'-biphenyl-2-yl)methyl]piperazin-1-y-
l}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)ami-
no]phenyl}sulfonyl)benzamide;
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pi-
perazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-
-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-
-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfon-
yl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]--
2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-ni-
trophenyl}sulfonyl)benzamide;
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pi-
perazin-1-yl]-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide;
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-
-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benza-
mide;
4-[4-({4'-chloro-4-[3-(dimethylamino)prop-1-ynyl]-1,1'-biphenyl-2-yl-
}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-
-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(l
1H-indol-4-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperidin-4-yl]-
amino}phenyl)sulfonyl]benzamide;
4-(4-{[4'-chloro-4-(2-hydroxyethoxy)-1,1'-biphenyl-2-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)-
amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trif-
luoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-
-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benza-
mide;
4-(4-{[4'-chloro-4-(2-hydroxyethoxy)-1,1'-biphenyl-2-yl]methyl}piper-
azin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-ni-
trophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]-
amino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitrop-
henyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}su-
lfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl-
)amino]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfonyl}ben-
zamide;
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H--
indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfony-
l)benzamide;
4-{4-[(1R)-1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-in-
dol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)benzamide;
4-{4-[(1S)-1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-in-
dol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulf-
onyl}benzamide;
4-[4-({4'-chloro-4-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pi-
perazin-1-yl]-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]a-
mino}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulf-
onyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy-
)phenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amin-
o}phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitr-
ophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[3-(methylsulfonyl)propyl]amino}-3-nitr-
ophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[3-(1,1-dioxidothiomorpholin-4-yl)propyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-3-nitrophenyl}sulfon-
yl)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}-3-ni-
trophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]--
3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sul-
fonyl)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromet-
hyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethox-
y)phenyl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yl
oxy)-N-({4-[3-(methylsulfonyl)propoxy]-3-nitrophenyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}s-
ulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-y-
loxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]ph-
enyl}sulfonyl)benzamide;
N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfony-
l)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;
N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-
-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-
-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino-
}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phe-
nyl}sulfonyl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trif-
luoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
4-(4-{[4-(4-chlorophenyl)-1-(3-hydroxypropyl)-1,2,5,6-tetrahydropyridin-3-
-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-
-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(-
4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-y-
l)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-{[6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]--
5-(1,3-thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitro-
phenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(methylsulfonyl)phenyl]sulfonyl}benzamid-
e;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfo-
nyl}-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfon-
yl}-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfo-
nyl}-2-(1H-indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H--
indol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3--
yl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}su-
lfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-2-(1H-indol-4-yloxy)benzamide; and therapeutically
acceptable salts, prodrugs, salts of prodrugs and metabolites
thereof.
In another aspect, the present invention provides compounds of
Formula (IV)
##STR00012## and therapeutically acceptable salts, prodrugs, salts
of prodrugs and metabolites thereof, wherein A.sup.1, B.sup.1,
D.sup.1, E.sup.1, Y.sup.1, R.sup.30, and R.sup.37 are as described
herein for Formula (I), n is 0, 1, 2, or 3; describing the number
of substituents on R.sup.26, and R.sup.100 is as described for
substituents on R.sup.6.
In one embodiment of Formula (IV), A.sup.1 is N. In another
embodiment of Formula (IV), A.sup.1 is C(A.sup.2). In another
embodiment of Formula (IV), A.sup.1 is C(A.sup.2), and A.sup.2 is
H.
In one embodiment of Formula (IV), B.sup.1 is R.sup.1, OR.sup.1,
SR.sup.1, SO.sub.2R.sup.1, NHR.sup.1, N(R.sup.1).sub.2, or
C(O)NHR.sup.1. In another embodiment of Formula (IV), B.sup.1 is
NHR.sup.1. In another embodiment of Formula (IV), B.sup.1 is
NHR.sup.1, and A.sup.1 is C(A.sup.2), and A.sup.2 is H. In another
embodiment of Formula (IV), B.sup.1 is OR.sup.1. In another
embodiment of Formula (IV), B.sup.1 is OR.sup.1, and A.sup.1 is
C(A.sup.2), and A.sup.2 is H.
In one embodiment of Formula (IV), D.sup.1 and E.sup.1 are H. In
another embodiment of Formula (IV), B.sup.1 is NHR.sup.1, and
A.sup.1 is C(A.sup.2), A.sup.2 is H, and D.sup.1 and E are H. In
another embodiment of Formula (IV), B.sup.1 is OR.sup.1, and
A.sup.1 is C(A.sup.2), A.sup.2 is H, and D.sup.1 and E.sup.1 are
H.
In one embodiment of Formula (IV), Y.sup.1 is H, CN, NO.sub.2, F,
Cl, Br, I, CF.sub.3, R.sup.17, NHC(O)R.sup.17, or C(O)NH.sub.2. In
another embodiment of Formula (IV), Y.sup.1 is NO.sub.2. In another
embodiment of Formula (IV), B.sup.1 is NHR.sup.1, and A.sup.1 is
C(A.sup.2), A.sup.2 is H, D.sup.1 and E.sup.1 are H, and Y.sup.1 is
NO.sub.2. In another embodiment of Formula (IV), Y.sup.1 is Cl. In
another embodiment of Formula (I), B.sup.1 is OR.sup.1, and A.sup.1
is C(A.sup.2), A.sup.2 is H, D.sup.1 and E.sup.1 are H, and Y.sup.1
is Cl.
In one embodiment of Formula (IV), R.sup.1 is R.sup.2, R.sup.3,
R.sup.4 or R.sup.5. In another embodiment of Formula (IV), R.sup.1
is R.sup.2, and R.sup.2 is phenyl.
In one embodiment of Formula (IV), R.sup.1 is R.sup.3, and R.sup.3
is heteroaryl. In another embodiment of Formula (IV), R.sup.3 is
triazolyl.
In one embodiment of Formula (IV), R.sup.1 is R.sup.4. In another
embodiment of Formula (IV), R.sup.1 is R.sup.4, and R.sup.4 is
cycloalkyl. In another embodiment of Formula (IV), R.sup.1 is
R.sup.4, and R.sup.4 is cyclohexyl. In another embodiment of
Formula (IV), R.sup.1 is R.sup.4, and R.sup.4 is heterocycloalkyl.
In another embodiment of Formula (IV), R.sup.1 is R.sup.4, and 4 is
8-azabicyclo[3.2.1]octane, azetidinyl, piperidinyl, piperazinyl,
pyrrolidinyl, morpholinyl, tetrahydropyranyl, or
tetrahydrothiophenyl. In another embodiment of Formula (IV),
R.sup.1 is R.sup.4, and R.sup.4 is heterocycloalkenyl. In another
embodiment of Formula (IV), R.sup.1 is R.sup.4, and R.sup.4 is
tetrahydropyridazinyl.
In one embodiment of Formula (IV), R.sup.1 is R.sup.5. In another
embodiment of Formula (IV), R.sup.1 is R.sup.5 and R.sup.5 is alkyl
or alkynyl. In another embodiment of Formula (IV), R.sup.1 is
R.sup.5 and R.sup.5 is alkyl which is unsubstituted. In another
embodiment of Formula (IV), R.sup.1 is R.sup.5 and R.sup.5 is alkyl
which is substituted with one or two or three independently
selected R.sup.6, R.sup.7, OR.sup.7, SR.sup.7, SO.sub.2R.sup.7,
N(R.sup.7).sub.2, OH, CN, CF.sub.3, F, Cl, Br or I substituents. In
another embodiment of Formula (IV), R.sup.1 is R.sup.5 and R.sup.5
is alkyl which is substituted with R.sup.7.
In one embodiment of Formula (IV), R.sup.7 is R.sup.8, R.sup.9,
R.sup.10 or R.sup.11. In another embodiment of Formula (IV),
R.sup.7 is R.sup.8, and R.sup.8 is phenyl which is unfused or fused
with R.sup.8A, and R.sup.8A is heterocycloalkane. In another
embodiment of Formula (IV), R.sup.7 is R.sup.8, and R.sup.8 is
phenyl which is unfused. In another embodiment of Formula (IV),
R.sup.7 is R.sup.9, and R.sup.9 is heteroaryl. In another
embodiment of Formula (IV), R.sup.7 is R.sup.9, and R.sup.9 is
furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,
1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,
pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl,
thiophenyl, triazinyl or 1,2,3-triazolyl. In another embodiment of
Formula (IV), R.sup.7 is R.sup.9, and R.sup.9 is pyridinyl,
thiazolyl, imidazoyl, and 1,2,3-triazolyl. In another embodiment of
Formula (IV), R.sup.7 is R.sup.10, and R.sup.10 is
C.sub.3-C.sub.10-cycloalkyl. In another embodiment of Formula (IV),
R.sup.7 is R.sup.10, and R.sup.10 is C.sub.6 or
C.sub.10-cycloalkyl. In another embodiment of Formula (IV), R.sup.7
is R.sup.10, and R.sup.10 is cyclohexyl or adamantanyl. In another
embodiment of Formula (IV), R.sup.7 is R.sup.10, and R.sup.10 is
morpholinyl, piperazinyl, piperidinyl, tetrahydro-2H-pyranyl,
1,2-dihydropyridinyl, pyranyl, pyridin-1(H)-yl, pyrrolidinyl,
oxetanyl, thiomorpholinyl, imidazolidinyl, tetrahydrothiophenyl,
dioxolanyl, tetrahydrothiopyranyl, dioxanyl, or tetrahydrofuranyl.
In another embodiment of Formula (IV), R.sup.7 is R.sup.10, and
R.sup.10 is morpholinyl, piperazinyl, piperidinyl,
tetrahydro-2H-pyranyl, 1,2-dihydropyridinyl, pyrrolidinyl,
oxetanyl, thiomorpholinyl, imidazolidinyl, tetrahydrothiophenyl,
dioxolanyl, tetrahydrothiopyranyl, dioxanyl, or tetrahydrofuranyl.
In another embodiment of Formula (IV), R.sup.7 is R.sup.11, and
R.sup.11 is alkyl which is unsubstituted or substituted. In another
embodiment of Formula (IV), R.sup.7 is R.sup.11, and R.sup.11 is
alkyl which is unsubstituted. In another embodiment of Formula
(IV), R.sup.7 is R.sup.11, and R.sup.11 is alkyl which is
substituted. In another embodiment of Formula (IV), R.sup.7 is
R.sup.11, and R.sup.11 is alkyl which is substituted within one or
two or three independently selected OR.sup.12, F, C.sub.1, Br or
substituents. In another embodiment of Formula (IV), R.sup.7 is
R.sup.11, R.sup.11 is alkyl which is substituted with OR.sup.12,
R.sup.12 is R.sup.16, and R.sup.16 is alkyl.
In one embodiment of Formula (IV), R.sup.17 is R.sup.19 or
R.sup.21. In another embodiment of Formula (IV), R.sup.17 is
R.sup.19, and R.sup.19 is heteroaryl. In another embodiment of
Formula (IV), R.sup.17 is R.sup.19, and R.sup.19 is thiazolyl. In
another embodiment of Formula (IV), R.sup.17 is R.sup.21, and
R.sup.21 is alkynyl. In another embodiment of Formula (IV),
R.sup.17 is R.sup.21, and R.sup.21 is ethynyl.
Still another embodiment pertains to compounds having Formula (IV)
which are
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrro-
lidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-y-
l)methoxy]-3-nitrophenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin-
-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-
-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)m-
orpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-
-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)m-
orpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-
-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin--
3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethy-
l]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrr-
olidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]-
methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)me-
thyl]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-oxetan-3-ylmorpholin-
-2-yl)methyl]amino}phenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)mor-
pholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)mor-
pholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmet-
hyl)amino]phenyl}sulfonyl)benzamide; Trans-2-(l
1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-
-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-
-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4--
yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H--
pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran--
4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)-
amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3--
nitrophenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)ami-
no]-3-nitrophenyl}sulfonyl)benzamide;
Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexy-
l)amino]-3-nitrophenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]-
amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({(2R)-4-[2-(2-methoxyethoxy)eth-
yl]morpholin-2-yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]-
amino}-3-nitrophenyl)sulfonyl]benzamide;
N-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(-
1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1--
en-1-yl]methyl}piperazin-1-yl)benzamide;
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2--
yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;
Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyanocyclohexyl)methyl-
]amino}-3-nitrophenyl)sulfonyl]benzamide;
2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4,4-difluorocyclohexyl)metho-
xy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-
-en-1-yl]methyl}piperazin-1-yl)benzamide; and therapeutically
acceptable salts, prodrugs, salts of prodrugs and metabolites
thereof.
In another aspect, the present invention provides compounds of
Formula (V)
##STR00013## and therapeutically acceptable salts, prodrugs, salts
of prodrugs and metabolites thereof, wherein A.sup.1, B.sup.1,
D.sup.1, E.sup.1, Y, R.sup.30, and R.sup.37 are as described herein
for Formula (I), n is 0, 1, 2, or 3; describing the number of
substituents on R.sup.26, and R.sup.100 is as described for
substituents on R.sup.26.
In one embodiment of Formula (V), A.sup.1 is N. In another
embodiment of Formula (V), A.sup.1 is C(A.sup.2). In another
embodiment of Formula (V), A.sup.1 is C(A.sup.2), and A.sup.2 is
H.
In one embodiment of Formula (V), B.sup.1 is R.sup.1, OR.sup.1,
SR.sup.1, SO.sub.2R.sup.1, NHR.sup.1, N(R.sup.1).sub.2, or
C(O)NHR.sup.1. In another embodiment of Formula (V), B.sup.1 is
NHR.sup.1. In another embodiment of Formula (V), B.sup.1 is
NHR.sup.1, and A.sup.1 is C(A.sup.2), and A.sup.2 is H. In another
embodiment of Formula (V), B.sup.1 is OR.sup.1. In another
embodiment of Formula (V), B.sup.1 is OR.sup.1, and A.sup.1 is
C(A.sup.2), and A.sup.2 is H.
In one embodiment of Formula (V), D.sup.1 and E.sup.1 are H. In
another embodiment of Formula (V), B.sup.1 is NHR.sup.1, and
A.sup.1 is C(A.sup.2), A.sup.2 is H, and D.sup.1 and E.sup.1 are H.
In another embodiment of Formula (V), B.sup.1 is OR.sup.1, and
A.sup.1 is C(A.sup.2), A.sup.2 is H, and D.sup.1 and E.sup.1 are
H.
In one embodiment of Formula (V), Y.sup.1 is H, CN, NO.sub.2, F,
Cl, Br, I, CF.sub.3, R.sup.17, NHC(O)R.sup.17, or C(O)NH.sub.2. In
another embodiment of Formula (V), Y.sup.1 is NO.sub.2. In another
embodiment of Formula (V), B.sup.1 is NHR.sup.1, and A.sup.1 is
C(A.sup.2), A.sup.2 is H, D.sup.1 and E.sup.1 are H, and Y.sup.1 is
NO.sub.2. In another embodiment of Formula (V), Y.sup.1 is Cl. In
another embodiment of Formula (I), B.sup.1 is OR.sup.1, and A.sup.1
is C(A.sup.2), A.sup.2 is H, D.sup.1 and E.sup.1 are H, and Y.sup.1
is Cl.
In one embodiment of Formula (V), R.sup.1 is R.sup.2, R.sup.3,
R.sup.4 or R.sup.5. In another embodiment of Formula (V), R.sup.1
is R.sup.2, and R.sup.2 is phenyl.
In one embodiment of Formula (V), R.sup.1 is R.sup.3, and R.sup.3
is heteroaryl. In another embodiment of Formula (V), R.sup.3 is
triazolyl.
In one embodiment of Formula (V), R.sup.1 is R.sup.4. In another
embodiment of Formula (V), R.sup.1 is R.sup.4, and R.sup.4 is
cycloalkyl. In another embodiment of Formula (V), R.sup.1 is
R.sup.4, and R.sup.4 is cyclohexyl. In another embodiment of
Formula (V), R.sup.1 is R.sup.4, and R.sup.4 is heterocycloalkyl.
In another embodiment of Formula (V), R.sup.1 is R.sup.4, and
R.sup.4 is 8-azabicyclo[3.2.1]octane, azetidinyl, piperidinyl,
piperazinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, or
tetrahydrothiophenyl. In another embodiment of Formula (V), R.sup.1
is R.sup.4, and R.sup.4 is heterocycloalkenyl. In another
embodiment of Formula (V), R.sup.1 is R.sup.4, and R.sup.4 is
tetrahydropyridazinyl.
In one embodiment of Formula (V), R.sup.1 is R.sup.5. In another
embodiment of Formula (V), R.sup.1 is R.sup.5 and R.sup.5 is alkyl
or alkynyl. In another embodiment of Formula (V), R.sup.1 is
R.sup.5 and R.sup.5 is alkyl which is unsubstituted. In another
embodiment of Formula (V), R.sup.1 is R.sup.5 and R.sup.5 is alkyl
which is substituted with one or two or three independently
selected R.sup.6, R.sup.7, OR.sup.7, SR.sup.7, SO.sub.2R.sup.7,
N(R.sup.7).sub.2, OH, CN, CF.sub.3, F, Cl, Br or I substituents. In
another embodiment of Formula (V), R.sup.1 is R.sup.5 and R.sup.5
is alkyl which is substituted with R.sup.7.
In one embodiment of Formula (V), R.sup.7 is R.sup.8, R.sup.9,
R.sup.10 or R.sup.11. In another embodiment of Formula (V), R.sup.7
is R.sup.8, and R.sup.8 is phenyl which is unfused or fused with
R.sup.8A, and R.sup.8A is heterocycloalkane. In another embodiment
of Formula (V), R.sup.7 is R.sup.8, and R.sup.8 is phenyl which is
unfused. In another embodiment of Formula (V), R.sup.7 is R.sup.9,
and R.sup.9 is heteroaryl. In another embodiment of Formula (V),
R.sup.7 is R.sup.9, and R.sup.9 is furanyl, imidazolyl,
isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl,
oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl,
pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl
or 1,2,3-triazolyl. In another embodiment of Formula (V), R.sup.7
is R.sup.9, and R.sup.9 is pyridinyl, thiazolyl, imidazoyl, and
1,2,3-triazolyl. In another embodiment of Formula (V), R.sup.7 is
R.sup.10, and R.sup.10 is C.sub.3-C.sub.10-cycloalkyl. In another
embodiment of Formula (V), R.sup.7 is R.sup.10, and R.sup.10 is
C.sub.6 or C.sub.10-cycloalkyl. In another embodiment of Formula
(V), R.sup.7 is R.sup.10, and R.sup.10 is cyclohexyl or
adamantanyl. In another embodiment of Formula (V), R.sup.7 is
R.sup.10, and R.sup.10 is morpholinyl, piperazinyl, piperidinyl,
tetrahydro-2H-pyranyl, 1,2-dihydropyridinyl, pyranyl,
pyridin-1(H)-yl, pyrrolidinyl, oxetanyl, thiomorpholinyl,
imidazolidinyl, tetrahydrothiophenyl, dioxolanyl,
tetrahydrothiopyranyl, dioxanyl, or tetrahydrofuranyl. In another
embodiment of Formula (V), R.sup.7 is R.sup.10, and R.sup.10 is
morpholinyl, piperazinyl, piperidinyl, tetrahydro-2H-pyranyl,
1,2-dihydropyridinyl, pyrrolidinyl, oxetanyl, thiomorpholinyl,
imidazolidinyl, tetrahydrothiophenyl, dioxolanyl,
tetrahydrothiopyranyl, dioxanyl, or tetrahydrofuranyl. In another
embodiment of Formula (V), R.sup.7 is R.sup.11, and R.sup.11 is
alkyl which is unsubstituted or substituted. In another embodiment
of Formula (V), R.sup.7 is R.sup.11, and R.sup.11 is alkyl which is
unsubstituted. In another embodiment of Formula (V), R.sup.7 is
R.sup.11, and R.sup.1 is alkyl which is substituted. In another
embodiment of Formula (V), R.sup.7 is R.sup.11, and R.sup.11 is
alkyl which is substituted with one or two or three independently
selected OR.sup.12, F, Cl, Br or I substituents.
In another embodiment of Formula (V), R.sup.7 is R.sup.11, R.sup.1
is alkyl which is substituted with OR.sup.12, R.sup.12 is R.sup.16,
and R.sup.16 is alkyl.
In one embodiment of Formula (V), R.sup.17 is R.sup.19 or R.sup.21.
In another embodiment of Formula (V), R.sup.17 is R.sup.19, and
R.sup.19 is heteroaryl. In another embodiment of Formula (V),
R.sup.17 is R.sup.19, and R.sup.19 is thiazolyl. In another
embodiment of Formula (V), R.sup.17 is R.sup.21, and R.sup.21 is
alkynyl. In another embodiment of Formula (V), R.sup.17 is
R.sup.21, and R.sup.21 is ethynyl.
Still another embodiment pertains to compounds having Formula (V)
which are
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-y-
l}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methy-
l}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3--
yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethy-
l)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)su-
lfonyl]-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfony-
l]-2-(1H-indazol-4-yloxy)benzamide;
N-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3-
-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
Trans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-
-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
4-(4-({[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin--
3-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;
N-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-
-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-chloro-6-(tetrahydrofuran-3-ylmethoxy)pyridin-3-yl]sulfonyl}--
2-(1H-indazol-4-yloxy)benzamide;
Trans-N-({5-chloro-6-[(4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-
-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3--
yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridi-
n-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]-
methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridi-
n-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]-
methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfon-
yl}-2-(1H-indazol-4-yloxy)benzamide;
N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}o-
xy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-
-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amin-
o)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-(1H-indazol-4-yloxy)benzamide;
N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}m-
ethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridi-
n-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]-
methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-indazol-4-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]am-
ino}-3-nitrophenyl)sulfonyl]benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indazo-
l-4-yloxy)benzamide;
N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-
-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)-
amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[6-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}m-
ethoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)be-
nzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}p-
iperazin-1-yl)-N-{[5-chloro-6-(2-tetrahydrofuran-2-ylethoxy)pyridin-3-yl]s-
ulfonyl}-2-(1H-indazol-4-yloxy)benzamide;
N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl-
)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}su-
lfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]m-
ethyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5-cyano-6-(2-tetrahydro-2H-pyran-4-ylethoxy)pyridin-3-yl]sulfon-
yl}-2-(1H-indazol-4-yloxy)benzamide; and therapeutically acceptable
salts, prodrugs, salts of prodrugs and metabolites thereof.
Pharmaceutical Compositions, Combination Therapies, Methods of
Treatment, and Administration
Another embodiment comprises pharmaceutical compositions comprising
a compound having Formula (I) and an excipient.
Still another embodiment comprises methods of treating cancer in a
mammal comprising administering thereto a therapeutically
acceptable amount of a compound having Formula (I).
Still another embodiment comprises methods of treating autoimmune
disease in a mammal comprising administering thereto a
therapeutically acceptable amount of a compound having Formula
(I).
Still another embodiment pertains to compositions for treating
diseases during which anti-apoptotic Bcl-2 proteins are expressed,
said compositions comprising an excipient and a therapeutically
effective amount of the compound having Formula (I).
Still another embodiment pertains to methods of treating disease in
a patient during which anti-apoptotic Bcl-2 proteins are expressed,
said methods comprising administering to the patient a
therapeutically effective amount of a compound having Formula
(I).
Still another embodiment pertains to compositions for treating
bladder cancer, brain cancer, breast cancer, bone marrow cancer,
cervical cancer, chronic lymphocytic leukemia, colorectal cancer,
esophageal cancer, hepatocellular cancer, lymphoblastic leukemia,
follicular lymphoma, lymphoid malignancies of T-cell or B-cell
origin, melanoma, myelogenous leukemia, myeloma, oral cancer,
ovarian cancer, non-small cell lung cancer, prostate cancer, small
cell lung cancer or spleen cancer, said compositions comprising an
excipient and a therapeutically effective amount of the compound
having Formula (I).
Still another embodiment pertains to methods of treating bladder
cancer, brain cancer, breast cancer, bone marrow cancer, cervical
cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal
cancer, hepatocellular cancer, lymphoblastic leukemia, follicular
lymphoma, lymphoid malignancies of T-cell or B-cell origin,
melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian
cancer, non-small cell lung cancer, prostate cancer, small cell
lung cancer or spleen cancer in a patient, said methods comprising
administering to the patient a therapeutically effective amount of
a compound having Formula (I).
Still another embodiment pertains to compositions for treating
diseases during which are expressed anti-apoptotic Bcl-2 proteins,
said compositions comprising an excipient and a therapeutically
effective amount of the compound having Formula (I) and a
therapeutically effective amount of one additional therapeutic
agent or more than one additional therapeutic agent.
Still another embodiment pertains to methods of treating disease in
a patient during which are expressed anti-apoptotic Bcl-2 proteins,
said methods comprising administering to the patient a
therapeutically effective amount of a compound having Formula (I)
and a therapeutically effective amount of one additional
therapeutic agent or more than one additional therapeutic
agent.
Still another embodiment pertains to compositions for treating
bladder cancer, brain cancer, breast cancer, bone marrow cancer,
cervical cancer, chronic lymphocytic leukemia, colorectal cancer,
esophageal cancer, hepatocellular cancer, lymphoblastic leukemia,
follicular lymphoma, lymphoid malignancies of T-cell or B-cell
origin, melanoma, myelogenous leukemia, myeloma, oral cancer,
ovarian cancer, non-small cell lung cancer, chronic lymphocytic
leukemia, myeloma, prostate cancer, small cell lung cancer or
spleen cancer, said compositions comprising an excipient and a
therapeutically effective amount of the compound having Formula (I)
and a therapeutically effective amount of one additional
therapeutic agent or more than one additional therapeutic
agent.
Still another embodiment pertains to methods of treating bladder
cancer, brain cancer, breast cancer, bone marrow cancer, cervical
cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal
cancer, hepatocellular cancer, lymphoblastic leukemia, follicular
lymphoma, lymphoid malignancies of T-cell or B-cell origin,
melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian
cancer, non-small cell lung cancer, chronic lymphocytic leukemia,
myeloma, prostate cancer, small cell lung cancer or spleen cancer
in a patient, said methods comprising administering to the patient
a therapeutically effective amount of the compound having Formula
(I) and a therapeutically effective amount of one additional
therapeutic agent or more than one additional therapeutic
agent.
Metabolites of compounds having Formula I, produced by in vitro or
in vivo metabolic processes, may also have utility for treating
diseases associated with anti-apoptotic Bcl-2 protein.
Certain precursor compounds which may be metabolized in vitro or in
vivo to form compounds having Formula I may also have utility for
treating diseases associated with expression of anti-apoptotic
Bcl-2 protein.
Compounds having Formula I may exist as acid addition salts, basic
addition salts or zwitterions. Salts of the compounds are prepared
during isolation or following purification of the compounds. Acid
addition salts of the compounds are those derived from the reaction
of the compounds with an acid. For example, the acetate, adipate,
alginate, bicarbonate, citrate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate,
digluconate, formate, fumarate, glycerophosphate, glutamate,
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,
hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonate,
methanesulfonate, naphthylenesulfonate, nicotinate, oxalate,
pamoate, pectinate, persulfate, phosphate, picrate, propionate,
succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic,
para-toluenesulfonate, and undecanoate salts of the compounds and
prodrugs thereof are contemplated as being embraced by this
invention. Basic addition salts of the compounds are those derived
from the reaction of the compounds with the hydroxide, carbonate or
bicarbonate of cations such as lithium, sodium, potassium, calcium,
and magnesium.
The compounds having Formula I may be administered, for example,
bucally, ophthalmically, orally, osmotically, parenterally
(intramuscularly, intraperitoneally intrasternally, intravenously,
subcutaneously), rectally, topically, transdermally, or
vaginally.
Therapeutically effective amounts of compounds having Formula I
depend on the recipient of the treatment, the disorder being
treated and the severity thereof, the composition containing the
compound, the time of administration, the route of administration,
the duration of treatment, the compound potency, its rate of
clearance and whether or not another drug is co-administered. The
amount of a compound of this invention having Formula I used to
make a composition to be administered daily to a patient in a
single dose or in divided doses is from about 0.03 to about 200
mg/kg body weight. Single dose compositions contain these amounts
or a combination of submultiples thereof.
Compounds having Formula I may be administered with or without an
excipient. Excipients include, for example, encapsulating materials
or additives such as absorption accelerators, antioxidants,
binders, buffers, coating agents, coloring agents, diluents,
disintegrating agents, emulsifiers, extenders, fillers, flavoring
agents, humectants, lubricants, perfumes, preservatives,
propellants, releasing agents, sterilizing agents, sweeteners,
solubilizers, wetting agents and mixtures thereof.
Excipients for preparation of compositions comprising a compound
having Formula I to be administered orally in solid dosage form
include, for example, agar, alginic acid, aluminum hydroxide,
benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers,
castor oil, cellulose, cellulose acetate, cocoa butter, corn
starch, corn oil, cottonseed oil, cross-povidone, diglycerides,
ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid
esters, gelatin, germ oil, glucose, glycerol, groundnut oil,
hydroxypropylmethyl cellulose, isopropanol, isotonic saline,
lactose, magnesium hydroxide, magnesium stearate, malt, mannitol,
monoglycerides, olive oil, peanut oil, potassium phosphate salts,
potato starch, povidone, propylene glycol, Ringer's solution,
safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium
phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean
oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc,
tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and
mixtures thereof. Excipients for preparation of compositions
comprising a compound of this invention having Formula I to be
administered ophthalmically or orally in liquid dosage forms
include, for example, 1,3-butylene glycol, castor oil, corn oil,
cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil,
groundnut oil, glycerol, isopropanol, olive oil, polyethylene
glycols, propylene glycol, sesame oil, water and mixtures thereof.
Excipients for preparation of compositions comprising a compound of
this invention having Formula I to be administered osmotically
include, for example, chlorofluorohydrocarbons, ethanol, water and
mixtures thereof. Excipients for preparation of compositions
comprising a compound of this invention having Formula I to be
administered parenterally include, for example, 1,3-butanediol,
castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut
oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's
solution, safflower oil, sesame oil, soybean oil, U.S.P. or
isotonic sodium chloride solution, water and mixtures thereof.
Excipients for preparation of compositions comprising a compound of
this invention having Formula I to be administered rectally or
vaginally include, for example, cocoa butter, polyethylene glycol,
wax and mixtures thereof.
Compounds having Formula (I) are expected to be useful when used
with alkylating agents, angiogenesis inhibitors, antibodies,
antimetabolites, antimitotics, antiproliferatives, antivirals,
aurora kinase inhibitors, other apoptosis promoters (for example,
Bcl-xL, Bcl-w and Bfl-1) inhibitors, activators of death receptor
pathway, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell
Engager) antibodies, antibody drug conjugates, biologic response
modifiers, cyclin-dependent kinase inhibitors, cell cycle
inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia viral
oncogene homolog (ErbB2) receptor inhibitors, growth factor
inhibitors, heat shock protein (HSP)-90 inhibitors, histone
deacetylase (HDAC) inhibitors, hormonal therapies, immunologicals,
inhibitors of inhibitors of apoptosis proteins (IAPs),
intercalating antibiotics, kinase inhibitors, kinesin inhibitors,
Jak2 inhibitors, mammalian target of rapamycin inhibitors,
microRNA's, mitogen-activated extracellular signal-regulated kinase
inhibitors, multivalent binding proteins, non-steroidal
anti-inflammatory drugs (NSAIDs), poly ADP (adenosine
diphosphate)-ribose polymerase (PARP) inhibitors, platinum
chemotherapeutics, polo-like kinase (Plk) inhibitors,
phosphoinositide-3 kinase (PI3K) inhibitors, proteosome inhibitors,
purine analogs, pyrimidine analogs, receptor tyrosine kinase
inhibitors, etinoids/deltoids plant alkaloids, small inhibitory
ribonucleic acids (siRNAs), topoisomerase inhibitors, ubiquitin
ligase inhibitors, and the like, and in combination with one or
more of these agents.
BiTE antibodies are bi-specific antibodies that direct T-cells to
attack cancer cells by simultaneously binding the two cells. The
T-cell then attacks the target cancer cell. Examples of BiTE
antibodies include adecatumumab (Micromet MT201), blinatumomab
(Micromet MT103) and the like. Without being limited by theory, one
of the mechanisms by which T-cells elicit apoptosis of the target
cancer cell is by exocytosis of cytolytic granule components, which
include perforin and granzyme B. In this regard, Bcl-2 has been
shown to attenuate the induction of apoptosis by both perforin and
granzyme B. These data suggest that inhibition of Bcl-2 could
enhance the cytotoxic effects elicited by T-cells when targeted to
cancer cells (V. R. Sutton, D. L. Vaux and J. A. Trapani, J. of
Immunology 1997, 158 (12), 5783).
SiRNAs are molecules having endogenous RNA bases or chemically
modified nucleotides. The modifications do not abolish cellular
activity, but rather impart increased stability and/or increased
cellular potency. Examples of chemical modifications include
phosphorothioate groups, 2'-deoxynucleotide,
2'-OCH.sub.3-containing ribonucleotides, 2'-F-ribonucleotides,
2'-methoxyethyl ribonucleotides, combinations thereof and the like.
The siRNA can have varying lengths (e.g., 10-200 bps) and
structures (e.g., hairpins, single/double strands, bulges,
nicks/gaps, mismatches) and are processed in cells to provide
active gene silencing. A double-stranded siRNA (dsRNA) can have the
same number of nucleotides on each strand (blunt ends) or
asymmetric ends (overhangs). The overhang of 1-2 nucleotides can be
present on the sense and/or the antisense strand, as well as
present on the 5'- and/or the 3'-ends of a given strand. For
example, siRNAs targeting Mcl-1 have been shown to enhance the
activity of ABT-263, (i.e.,
N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)pip-
erazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl-
)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide) or
ABT-737 (i.e.,
N-(4-(4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl)benz-
oyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3--
nitrobenzenesulfonamide) in multiple tumor cell lines (Tse et. al,
Cancer Research 2008, 68(9), 3421 and references therein).
Multivalent binding proteins are binding proteins comprising two or
more antigen binding sites. Multivalent binding proteins are
engineered to have the three or more antigen binding sites and are
generally not naturally occurring antibodies. The term
"multispecific binding protein" means a binding protein capable of
binding two or more related or unrelated targets. Dual variable
domain (DVD) binding proteins are tetravalent or multivalent
binding proteins binding proteins comprising two or more antigen
binding sites. Such DVDs may be monospecific (i.e., capable of
binding one antigen) or multispecific (i.e., capable of binding two
or more antigens). DVD binding proteins comprising two heavy chain
DVD polypeptides and two light chain DVD polypeptides are referred
to as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVD
polypeptide, a light chain DVD polypeptide, and two antigen binding
sites. Each binding site comprises a heavy chain variable domain
and a light chain variable domain with a total of 6 CDRs involved
in antigen binding per antigen binding site. Multispecific DVDs
include DVD binding proteins that bind DLL4 and VEGF, or C-met and
EFGR or ErbB3 and EGFR.
Alkylating agents include altretamine, AMD-473, AP-5280,
apaziquone, bendamustine, brostallicin, busulfan, carboquone,
carmustine (BCNU), chlorambucil, CLORETAZINE (laromustine, VNP
40101M), cyclophosphamide, decarbazine, estramustine, fotemustine,
glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide,
melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard
N-oxide, ranimustine, temozolomide, thiotepa, TREANDA.RTM.
(bendamustine), treosulfan, rofosfamide and the like.
Angiogenesis inhibitors include endothelial-specific receptor
tyrosine kinase (Tie-2) inhibitors, epidermal growth factor
receptor (EGFR) inhibitors, insulin growth factor-2 receptor
(IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors,
matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived
growth factor receptor (PDGFR) inhibitors, thrombospondin analogs,
vascular endothelial growth factor receptor tyrosine kinase (VEGFR)
inhibitors and the like.
Antimetabolites include ALIMTA.RTM. (pemetrexed disodium, LY231514,
MTA), 5-azacitidine, XELODA.RTM. (capecitabine), carmofur,
LEUSTAT.RTM. (cladribine), clofarabine, cytarabine, cytarabine
ocfosfate, cytosine arabinoside, decitabine, deferoxamine,
doxifluridine, eflornithine, EICAR
(5-ethynyl-1-.beta.-D-ribofuranosylimidazole-4-carboxamide),
enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or
in combination with leucovorin, GEMZAR.RTM. (gemcitabine),
hydroxyurea, ALKERAN.RTM. (melphalan), mercaptopurine,
6-mercaptopurine riboside, methotrexate, mycophenolic acid,
nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,
raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,
tegafur, TS-1, vidarabine, UFT and the like.
Antivirals include ritonavir, hydroxychloroquine and the like.
Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054.
VX-680, Aurora A-specific kinase inhibitors, Aurora B-specific
kinase inhibitors and pan-Aurora kinase inhibitors and the
like.
Bcl-2 protein inhibitors include AT-101 ((-)gossypol),
GENASENSE.RTM. (G3139 or oblimersen (Bcl-2-targeting antisense
oligonucleotide)), IPI-194, IPI-565,
N-(4-(4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4--
(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobe-
nzenesulfonamide) (ABT-737),
N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)pip-
erazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl-
)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide
(ABT-263), GX-070 (obatoclax) and the like.
Bcr-Abl kinase inhibitors include DASATINIB.RTM. (BMS-354825),
GLEEVEC.RTM. (imatinib) and the like.
CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387,
CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509,
seliciclib (CYC-202, R-roscovitine), ZK-304709 and the like.
COX-2 inhibitors include ABT-963, ARCOXIA.RTM. (etoricoxib),
BEXTRA.RTM. (valdecoxib), BMS347070, CELEBREX.RTM. (celecoxib),
COX-189 (lumiracoxib), CT-3, DERAMAXX.RTM. (deracoxib), JTE-522,
4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole),
MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125,
SD-8381, SVT-2016, S-2474, T-614, VIOXX.RTM. (rofecoxib) and the
like.
EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes,
EGF-vaccine, EMD-7200, ERBITUX.RTM. (cetuximab), HR3, IgA
antibodies, IRESSA.RTM. (gefitinib), TARCEVA.RTM. (erlotinib or
OSI-774), TP-38, EGFR fusion protein, TYKERB.RTM. (lapatinib) and
the like.
ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),
HERCEPTIN.RTM. (trastuzumab), TYKERB.RTM. (lapatinib),
OMNITARG.RTM. (2C4, petuzumab), TAK-165, GW-572016 (ionafarnib),
GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER-2
vaccine), anti-HER/2neu bispecific antibody, B7.her2IgG3, AS HER2
trifunctional bispecfic antibodies, mAB AR-209, mAB 2B-1 and the
like.
Histone deacetylase inhibitors include depsipeptide, LAQ-824,
MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA,
valproic acid and the like.
HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010,
CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB.RTM.
(human recombinant antibody to HSP-90), NCS-683664, PU24FCl, PU-3,
radicicol, SNX-2112, STA-9090 VER49009 and the like.
Inhibitors of inhibitors of apoptosis proteins include HGS1029,
GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.
Antibody drug conjugates include anti-CD22-MC-MMAF,
anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC,
MEDI-547, SGN-19Am SGN-35, SGN-75 and the like Activators of death
receptor pathway include TRAIL, antibodies or other agents that
target TRAIL or death receptors (e.g., DR4 and DR5) such as Apomab,
conatumumab, ETR2-ST01, GDC0145, (lexatumumab), HGS-1029, LBY-135,
PRO-1762 and trastuzumab.
Kinesin inhibitors include Eg5 inhibitors such as AZD4877,
ARRY-520; CENPE inhibitors such as GSK923295A and the like.
JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and
INCB018424 and the like.
MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059
and the like.
mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001,
rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors,
including PI-103, PP242, PP30, Torin 1 and the like.
Non-steroidal anti-inflammatory drugs include AMIGESIC.RTM.
(salsalate), DOLOBID.RTM. (diflunisal), MOTRIN.RTM. (ibuprofen),
ORUDIS.RTM. (ketoprofen), RELAFEN.RTM. (nabumetone), FELDENE.RTM.
(piroxicam), ibuprofen cream, ALEVE.RTM. (naproxen) and
NAPROSYN.RTM. (naproxen), VOLTAREN.RTM. (diclofenac), INDOCIN.RTM.
(indomethacin), CLINORIL.RTM. (sulindac), TOLECTIN.RTM. (tolmetin),
LODINE.RTM. (etodolac), TORADOL.RTM. (ketorolac), DAYPRO.RTM.
(oxaprozin) and the like.
PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.
Platinum chemotherapeutics include cisplatin, ELOXATIN.RTM.
(oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN.RTM.
(carboplatin), satraplatin, picoplatin and the like.
Polo-like kinase inhibitors include BI-2536 and the like.
Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin,
LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866,
GDC-0941, BGT226, BEZ235, XL765 and the like.
Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and
the like.
VEGFR inhibitors include AVASTIN.RTM. (bevacizumab), ABT-869,
AEE-788, ANGIOZYME.TM. (a ribozyme that inhibits angiogenesis
(Ribozyme Pharmaceuticals (Boulder, Colo.) and Chiron, (Emeryville,
Calif.)), axitinib (AG-13736), AZD-2171, CP-547,632, IM-862,
MACUGEN (pegaptamib), NEXAVAR.RTM. (sorafenib, BAY.sup.43-9006),
pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT.RTM.
(sunitinib, SU-11248), VEGF trap, ZACTIMA.TM. (vandetanib,
ZD-6474), GA101, ofatumumab, ABT-806 (mAb-806), ErbB3 specific
antibodies, BSG2 specific antibodies, DLL4 specific antibodies and
C-met specific antibodies, and the like.
Antibiotics include intercalating antibiotics aclarubicin,
actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE.RTM.
(bleomycin), daunorubicin, CAELYX.RTM. or MYOCET.RTM. (liposomal
doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS.RTM.
(idarubicin), mitomycin C, nemorubicin, neocarzinostatin,
peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin,
VALSTAR.RTM. (valrubicin), zinostatin and the like.
Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin,
amonafide, amsacrine, becatecarin, belotecan, BN-80915,
CAMPTOSAR.RTM. (irinotecan hydrochloride), camptothecin,
CARDIOXANE.RTM. (dexrazoxine), diflomotecan, edotecarin,
ELLENCE.RTM. or PHARMORUBICIN.RTM. (epirubicin), etoposide,
exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,
mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan,
sobuzoxane, SN-38, tafluposide, topotecan and the like.
Antibodies include AVASTIN.RTM. (bevacizumab), CD40-specific
antibodies, chTNT-1/B, denosumab, ERBITUX.RTM. (cetuximab),
HUMAX-CD4.RTM. (zanolimumab), IGF1R-specific antibodies,
lintuzumab, PANOREX.RTM. (edrecolomab), RENCAREX.RTM. (WX G250),
RITUXAN.RTM. (rituximab), ticilimumab, trastuzimab, CD20 antibodies
types I and II and the like.
Hormonal therapies include ARIMIDEX.RTM. (anastrozole),
AROMASIN.RTM. (exemestane), arzoxifene, CASODEX.RTM.
(bicalutamide), CETROTIDE.RTM. (cetrorelix), degarelix, deslorelin,
DESOPAN.RTM. (trilostane), dexamethasone, DROGENIL.RTM.
(flutamide), EVISTA.RTM. (raloxifene), AFEMA.TM. (fadrozole),
FARESTON.RTM. (toremifene), FASLODEX.RTM. (fulvestrant),
FEMARA.RTM. (letrozole), formestane, glucocorticoids, HECTOROL.RTM.
(doxercalciferol), RENAGEL.RTM. (sevelamer carbonate),
lasofoxifene, leuprolide acetate, MEGACE.RTM. (megesterol),
MIFEPREX.RTM. (mifepristone), NILANDRON.TM. (nilutamide),
NOLVADEX.RTM. (tamoxifen citrate), PLENAXIS.TM. (abarelix),
prednisone, PROPECIA.RTM. (finasteride), rilostane, SUPREFACT)
(buserelin), TRELSTAR.RTM. (luteinizing hormone releasing hormone
(LHRH)), VANTAS.RTM. (Histrelin implant), VETORYL.RTM. (trilostane
or modrastane), ZOLADEX.RTM.(fosrelin, goserelin) and the like.
Deltoids and retinoids include seocalcitol (EB1089, CB1093),
lexacalcitrol (KH1060), fenretinide, PANRETIN.RTM. (aliretinoin),
ATRAGEN.RTM. (liposomal tretinoin), TARGRETIN.RTM. (bexarotene),
LGD-1550 and the like.
PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436,
AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the
like.
Plant alkaloids include, but are not limited to, vincristine,
vinblastine, vindesine, vinorelbine and the like.
Proteasome inhibitors include VELCADE.RTM. (bortezomib), MG132,
NPI-0052, PR-171 and the like.
Examples of immunologicals include interferons and other
immune-enhancing agents.
Interferons include interferon alpha, interferon alpha-2a,
interferon alpha-2b, interferon beta, interferon gamma-1a,
ACTIMMUNE.RTM. (interferon gamma-1 b) or interferon gamma-n1,
combinations thereof and the like. Other agents include
ALFAFERONE.RTM., (IFN-.alpha.), BAM-002 (oxidized glutathione),
BEROMUN.RTM. (tasonermin), BEXXAR.RTM. (tositumomab), CAMPATH.RTM.
(alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine,
denileukin, epratuzumab, GRANOCYTE.RTM. (lenograstim), lentinan,
leukocyte alpha interferon, imiquimod, MDX-010 (anti-CTLA-4),
melanoma vaccine, mitumomab, molgramostim, MYLOTARG.TM. (gemtuzumab
ozogamicin), NEUPOGEN.RTM. (filgrastim), OncoVAC-CL, OVAREX.RTM.
(oregovomab), pemtumomab (Y-muHMFG1), PROVENGE.RTM.(sipuleucel-T),
sargaramostim, sizofilan, teceleukin, THERACYS.RTM. (Bacillus
Calmette-Guerin), ubenimex, VIRULIZIN.RTM. (immunotherapeutic,
Lorus Pharmaceuticals), Z-100 (Specific Substance of Maruyama
(SSM)), WF-10 (Tetrachlorodecaoxide (TCDO)), PROLEUKIN.RTM.
(aldesleukin), ZADAXIN.RTM. (thymalfasin), ZENAPAX.RTM.
(daclizumab), ZEVALIN.RTM. (90Y-Ibritumomab tiuxetan) and the
like.
Biological response modifiers are agents that modify defense
mechanisms of living organisms or biological responses, such as
survival, growth or differentiation of tissue cells to direct them
to have anti-tumor activity and include krestin, lentinan,
sizofiran, picibanil PF-3512676 (CpG-8954), ubenimex and the
like.
Pyrimidine analogs include cytarabine (ara C or Arabinoside C),
cytosine arabinoside, doxifluridine, FLUDARA.RTM. (fludarabine),
5-FU (5-fluorouracil), floxuridine, GEMZAR.RTM. (gemcitabine),
TOMUDEX.RTM. (ratitrexed), TROXATYL.TM. (triacetyluridine
troxacitabine) and the like.
Purine analogs include LANVIS.RTM. (thioguanine) and
PURI-NETHOL.RTM. (mercaptopurine).
Antimitotic agents include batabulin, epothilone D (KOS-862),
N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,
ixabepilone (BMS 247550), paclitaxel, TAXOTERE.RTM. (docetaxel),
PNU100940 (109881), patupilone, XRP-9881 (larotaxel), vinflunine,
ZK-EPO (synthetic epothilone) and the like.
Ubiquitin ligase inhibitors include MDM2 inhibitors, such as
nutlins, NEDD8 inhibitors such as MLN4924 and the like.
Compounds of this invention can also be used as radiosensitizers
that enhance the efficacy of radiotherapy. Examples of radiotherapy
include external beam radiotherapy, teletherapy, brachytherapy and
sealed, unsealed source radiotherapy and the like.
Additionally, compounds having Formula (I) may be combined with
other chemotherapeutic agents such as ABRAXANE.TM. (ABI-007),
ABT-100 (farnesyl transferase inhibitor), ADVEXIN.RTM. (Ad5CMV-p53
vaccine), ALTOCOR.RTM. or MEVACOR.RTM. (lovastatin), AMPLIGEN.RTM.
(poly I:poly C12U, a synthetic RNA), APTOSYN.RTM. (exisulind),
AREDIA.RTM. (pamidronic acid), arglabin, L-asparaginase, atamestane
(1-methyl-3,17-dione-androsta-1,4-diene), AVAGE.RTM. (tazarotene),
AVE-8062 (combreastatin derivative) BEC2 (mitumomab), cachectin or
cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC.RTM.
(cancer vaccine), CELEUK.RTM. (celmoleukin), CEPLENE.RTM.
(histamine dihydrochloride), CERVARIX.RTM. (human papillomavirus
vaccine), CHOP.RTM. (C: CYTOXAN.RTM. (cyclophosphamide); H:
ADRIAMYCIN.RTM. (hydroxydoxorubicin); O: Vincristine
(ONCOVIN.RTM.); P: prednisone), CYPAT.TM. (cyproterone acetate),
combrestatin A4P, DAB(389)EGF (catalytic and translocation domains
of diphtheria toxin fused via a His-Ala linker to human epidermal
growth factor) or TransMID-107R.TM. (diphtheria toxins),
dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid
(DMXAA), eniluracil, EVIZON.TM. (squalamine lactate),
DIMERICINE.RTM. (T4N5 liposome lotion), discodermolide, DX-8951f
(exatecan mesylate), enzastaurin, EP0906 (epithilone B),
GARDASIL.RTM. (quadrivalent human papillomavirus (Types 6, 11, 16,
18) recombinant vaccine), GASTRIMMUNE.RTM., GENASENSE.RTM., GMK
(ganglioside conjugate vaccine), GVAX.RTM. (prostate cancer
vaccine), halofuginone, histerelin, hydroxycarbamide, ibandronic
acid, IGN-101, IL-13-PE38, IL-13-PE3 8QQR (cintredekin besudotox),
IL-13-pseudomonas exotoxin, interferon-.alpha., interferon-7,
JUNOVAN.TM. or MEPACT.TM. (mifamurtide), lonafarnib,
5,10-methylenetetrahydrofolate, miltefosine
(hexadecylphosphocholine), NEOVASTAT.RTM.(AE-941), NEUTREXIN.RTM.
(trimetrexate glucuronate), NIPENT.RTM. (pentostatin), ONCONASE (a
ribonuclease enzyme), ONCOPHAGE.RTM. (melanoma vaccine treatment),
ONCOVAX (IL-2 Vaccine), ORATHECIN.TM. (rubitecan), OSIDEM.RTM.
(antibody-based cell drug), OVAREX.RTM. MAb (murine monoclonal
antibody), paclitaxel, PANDIMEX.TM. (aglycone saponins from ginseng
comprising 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol
(aPPT)), panitumumab, PANVAC.RTM.-VF (investigational cancer
vaccine), pegaspargase, PEG Interferon A, phenoxodiol,
procarbazine, rebimastat, REMOVAB.RTM. (catumaxomab),
REVLIMID.RTM.(lenalidomide), RSR13 (efaproxiral), SOMATULINE.RTM.
LA (lanreotide), SORIATANE.RTM. (acitretin), staurosporine
(Streptomyces staurospores), talabostat (PT100), TARGRETIN.RTM.
(bexarotene), TAXOPREXIN (DHA-paclitaxel), TELCYTA.RTM.
(canfosfamide, TLK286), temilifene, TEMODAR.RTM. (temozolomide),
tesmilifene, thalidomide, THERATOPE.RTM. (STn-KLH), thymitaq
(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazoline
dihydrochloride), TNFERADE.TM. (adenovector: DNA carrier containing
the gene for tumor necrosis factor-.alpha.), TRACLEER.RTM. or
ZAVESCA.RTM. (bosentan), tretinoin (Retin-A), tetrandrine, TRISENOX
(arsenic trioxide), VIRULIZIN.RTM., ukrain (derivative of alkaloids
from the greater celandine plant), vitaxin (anti-alphavbeta3
antibody), XCYTRIN.RTM. (motexafin gadolinium), XINLAY.TM.
(atrasentan), XYOTAX.TM. (paclitaxel poliglumex), YONDELIS.RTM.
(trabectedin), ZD-6126, ZINECARD.RTM. (dexrazoxane), ZOMETA.RTM.
(zolendronic acid), zorubicin and the like.
Data
Determination of the utility of compounds having Formula I as
binders to and inhibitors of anti-apoptotic Bcl-2 and Bcl-xL
proteins was performed using the Time Resolved-Fluorescence
Resonance Energy Transfer (TR-FRET) Assay. Tb-anti-GST antibody was
purchased from Invitrogen (Catalog No. PV4216).
Probe Synthesis
All reagents were used as obtained from the vendor unless otherwise
specified. Peptide synthesis reagents including
diisopropylethylamine (DIEA), dichloromethane (DCM),
N-methylpyrrolidone (NMP),
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HBTU), N-hydroxybenzotriazole (HOBt) and
piperidine were obtained from Applied Biosystems, Inc. (ABI),
Foster City, Calif. or American Bioanalytical, Natick, Mass.
Preloaded 9-Fluorenylmethyloxycarbonyl (Fmoc) amino acid cartridges
(Fmoc-Ala-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH,
Fmoc-Phe-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH,
Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Met-OH, Fmoc-Asn(Trt)-OH,
Fmoc-Pro-OH, Fmor-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Ser(tBu)-OH,
Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH)
were obtained from ABI or Anaspec, San Jose, Calif. The peptide
synthesis resin (Fmoc-Rink amide MBHA resin) and Fmoc-Lys(Mtt)-OH
were obtained from Novabiochem, San Diego, Calif. Single-isomer
6-carboxyfluorescein succinimidyl ester (6-FAM-NHS) was obtained
from Anaspec. Trifluoroacetic acid (TFA) was obtained from Oakwood
Products, West Columbia, S.C. Thioanisole, phenol,
triisopropylsilane (TIS), 3,6-dioxa-1,8-octanedithiol (DODT) and
isopropanol were obtained from Aldrich Chemical Co., Milwaukee,
Wis. Matrix-assisted laser desorption ionization mass-spectra
(MALDI-MS) were recorded on an Applied Biosystems Voyager DE-PRO
MS). Electrospray mass-spectra (ESI-MS) were recorded on Finnigan
SSQ7000 (Finnigan Corp., San Jose, Calif.) in both positive and
negative ion mode.
General Procedure for Solid-Phase Peptide Synthesis (SPPS)
Peptides were synthesized with, at most, 250 .mu.mol preloaded Wang
resin/vessel on an ABI 433A peptide synthesizer using 250 .mu.mol
scale Fastmoc.TM. coupling cycles. Preloaded cartridges containing
1 mmol standard Fmoc-amino acids, except for the position of
attachment of the fluorophore, where 1 mmol Fmoc-Lys(Mtt)-OH was
placed in the cartridge, were used with conductivity feedback
monitoring. N-terminal acetylation was accomplished by using 1 mmol
acetic acid in a cartridge under standard coupling conditions.
Removal of 4-Methyltrityl (Mtt) from Lysine
The resin from the synthesizer was washed thrice with
dichloromethane and kept wet. 150 mL of 95:4:1
dichloromethane:triisopropylsilane:trifluoroacetic acid was flowed
through the resin bed over 30 minutes. The mixture turned deep
yellow then faded to pale yellow. 100 mL of DMF was flowed through
the bed over 15 minutes. The resin was then washed thrice with DMF
and filtered. Ninhydrin tests showed a strong signal for primary
amine.
Resin Labeling with 6-Carboxyiluorescein-NHS (6-FAM-NHS)
The resin was treated with 2 equivalents 6-FAM-NHS in 1% DIEA/DMF
and stirred or shaken at ambient temperature overnight. When
complete, the resin was drained, washed thrice with DMF, thrice
with (1% DCM and 1% methanol) and dried to provide an orange resin
that was negative by ninhydrin test.
General Procedure for Cleavage and Deprotection of Resin-Bound
Peptide
Peptides were cleaved from the resin by shaking for 3 hours at
ambient temperature in a cleavage cocktail consisting of 80% TFA,
5% water, 5% thioanisole, 5% phenol, 2.5% TIS, and 2.5% EDT (1
mL/0.1 g resin). The resin was removed by filtration and rinsing
twice with TFA. The TFA was evaporated from the filtrates, and
product was precipitated with ether (10 mL/0.1 g resin), recovered
by centrifugation, washed twice with ether (10 mL/0.1 g resin) and
dried to give the crude peptide.
General Procedure for Purification of Peptides
The crude peptides were purified on a Gilson preparative HPLC
system running Unipoint.RTM. analysis software (Gilson, Inc.,
Middleton, Wis.) on a radial compression column containing two
25.times.100 mm segments packed with Delta-Pak.TM. C18 15 .mu.m
particles with 100 .ANG. pore size and eluted with one of the
gradient methods listed below. One to two milliliters of crude
peptide solution (10 mg/mL in 90% DMSO/water) was purified per
injection. The peaks containing the product(s) from each run were
pooled and lyophilized. All preparative runs were run at 20 mL/min
with eluents as buffer A: 0.1% TFA-water and buffer B:
acetonitrile.
General Procedure for Analytical HPLC
Analytical HPLC was performed on a Hewlett-Packard 1200 series
system with a diode-array detector and a Hewlett-Packard 1046A
fluorescence detector running HPLC 3D ChemStation software version
A.03.04 (Hewlett-Packard. Palo Alto, Calif.) on a 4.6.times.250 mm
YMC column packed with ODS-AQ 5 .mu.m particles with a 120 .ANG.
pore size and eluted with one of the gradient methods listed below
after preequilibrating at the starting conditions for 7 minutes.
Eluents were buffer A: 0.1% TFA-water and buffer B: acetonitrile.
The flow rate for all gradients was 1 mL/min.
F-Bak: Peptide Probe: Acetyl-(SEQ ID NO:
1)GQVGRQLAIIGDK(6-FAM)-(SEQ ID NO: 2) INR-NH.sub.2
Fmoc-Rink amide MBHA resin was extended using the general peptide
synthesis procedure to provide the protected resin-bound peptide
(1.020 g). The Mtt group was removed, labeled with 6-FAM-NHS and
cleaved and deprotected as described hereinabove to provide the
crude product as an orange solid (0.37 g). This product was
purified by RP-HPLC. Fractions across the main peak were tested by
analytical RP-HPLC, and the pure fractions were isolated and
lyophilized, with the major peak providing the title compound
(0.0802 g) as a yellow solid; MALDI-MS m/z=2137.1
((M+H).sup.-).
Alternative Synthesis of Peptide Probe F-Bak: Acetyl-(SEQ ID NO:
1)GQVGRQLAIIGDK(6-FAM)-1-(SEQ ID NO: 2)INR-NH.sub.2
The protected peptide was assembled on 0.25 mmol Fmoc-Rink amide
MBHA resin (Novabiochem) on an Applied Biosystems 433A automated
peptide synthesizer running Fastmoc.TM. coupling cycles using
pre-loaded 1 mmol amino acid cartridges, except for the fluorescein
(6-FAM)-labeled lysine, where 1 mmol Fmoc-Lys(4-methyltrityl) was
weighed into the cartridge. The N-terminal acetyl group was
incorporated by putting 1 mmol acetic acid in a cartridge and
coupling as described hereinabove. Selective removal of the
4-methyltrityl group was accomplished with a solution of 95:4:1
DCM:TIS:TFA (v/v/v) flowed through the resin over 15 minutes,
followed by quenching with a flow of dimethylformamide.
Single-isomer 6-carboxyfluorescein-NHS was reacted with the lysine
side-chain in 1% DIEA in DMF and confirmed complete by ninhydrin
testing. The peptide was cleaved from the resin and side-chains
deprotected by treating with 80:5:5:5:2.5:2.5
TFA:water:phenol:thioanisole:triisopropylsilane:3,6-dioxa-1,8-octanedithi-
ol (v/v/v/v/v/v), and the crude peptide was recovered by
precipitation with diethyl ether. The crude peptide was purified by
reverse-phase high-performance liquid chromatography, and its
purity and identity were confirmed by analytical reverse-phase
high-performance liquid chromatography and matrix-assisted
laser-desorption mass-spectrometry (m/z=2137.1 ((M+H)+)).
Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET)
Assay
Representative compounds were serially diluted in dimethyl
sulfoxide (DMSO) starting at 50 .mu.M (2.times. starting
concentration; 10% DMSO) and 10 .mu.L were transferred into a
384-well plate. Then 10 .mu.L of a protein/probe/antibody mix was
added to each well at final concentrations listed in TABLE 1.
TABLE-US-00001 TABLE 1 Protein, Probe And Antibody Used For TR-FRET
Assays Protein Probe Antibody Protein Probe (nM) (nM) Antibody (nM)
GST- F-Bak(SEQ. ID. No. 1) 1 100 Tb-anti- 1 Bcl-2 (GQVGRQLAIIGDK(6-
GST FAM) (SEQ ID No.2)INR-amide) GST- F-Bak(SEQ. ID. No. 1) 1 100
Tb-anti- 1 Bcl-X.sub.L (GQVGRQLAIIGDK(6- GST FAM) (SEQ ID
No.2)INR-amide) 6-FAM = 6-carboxyfluorescein.; Tb = terbium; GST =
glutathione S-transferase
The samples were then mixed on a shaker for 1 minute and incubated
for an additional 3 hours at room temperature. For each assay, the
probe/antibody and protein/probe/antibody were included on each
assay plate as negative and positive controls, respectively.
Fluorescence was measured on the Envision (Perkin Elmer) using a
340/35 nm excitation filter and 520/525 (F-Bak peptide) and 495/510
nm (Tb-labeled anti-Histidine antibody) emission filters.
Inhibition constants (K.sub.i) for compounds according to the
invention and ABT-737, and the binding selectivity ratio
(Bcl-X.sub.L K.sub.i:Bcl-2 K.sub.i) for each are shown in TABLE 2
below. The inhibition constant (K.sub.i) is the dissociation
constant of an enzyme-inhibitor complex or a protein/small molecule
complex, wherein the small molecule is inhibiting binding of one
protein to another protein or peptide. Where the K.sub.i for a
compound is represented as ">" (greater than) a certain
numerical value, it is intended to mean that the binding affinity
value (e.g., for Bcl-X.sub.L) is greater than the limits of
detection of the assay used. Where the binding selectivity ratio
for a compound is represented as ">" (greater than) a certain
numerical value, it is intended to mean that the selectivity of a
particular compound for Bcl-2 over Bcl-X.sub.L is at least as great
as the number indicated. Where the K.sub.i for a compound is
represented as "<" (less than) a certain numerical value, it is
intended to mean that the binding affinity value (e.g., for Bcl-2)
is lower than the limit of detection of the assay used. Inhibition
constants were determined using Wang's equation (Wang Z-X., An
Exact Mathematical Expression For Describing Competitive Binding Of
Two Different Ligands To A Protein Molecule. FEBS Lett. 1995,
360:111-4).
TABLE-US-00002 TABLE 2 TR-FRET Binding Affinity Binding selectivity
ratio (Bcl-X.sub.L Bcl-2 K.sub.i, Bcl-X.sub.L K.sub.i K.sub.i/Bcl-2
Example (.mu.M) (.mu.M) K.sub.i) ABT-737 0.000088 0.00008 0.9 1
0.006773 0.57833 85.4 18 0.000238 0.008131 34.2 19 0.000847
0.020027 23.6 20 0.002365 0.077593 32.8 21 0.005428 0.19038 35.1 22
0.006218 0.1253 20.2 23 0.006639 0.16782 25.3 24 0.000194 >0.66
>3402.1 25 0.00005 0.20519 4103.8 26 0.00014 >0.66 >4714.3
28 0.033705 >0.66 >19.6 29 0.011911 >0.66 >55.4 30
0.10292 >0.66 >6.4 31 0.036614 >0.66 >18.0 32 0.061123
>0.66 >10.8 33 0.006684 0.33339 49.9 34 0.001986 0.088007
44.3 36 0.000796 0.008995 11.3 37 0.000464 0.044422 95.7 40
0.000534 >0.66 >1236.0 42 0.000048 0.003841 80 45 0.000828
>0.66 >797.1 46 0.000159 0.018958 119.2 47 0.00663 0.10428
15.7 50 0.000471 0.090073 191.2 51 0.000252 0.015646 62.1 52
0.000239 0.079805 333.9 53 0.000081 0.004845 59.8 54 0.000757
0.082015 108.3 55 0.000196 0.02488 126.9 56 0.000268 0.012924 48.2
57 0.000068 0.004674 68.7 58 0.001085 0.28807 265.5 59 0.000672
1.255 1867.6 60 0.01893 >0.66 >34.9 61 0.05221 >0.66
>12.6 62 0.003516 0.5711 162.4 64 0.000523 0.040334 77.1 65
0.004558 0.021805 4.8 67 0.28867 >0.66 >2.3 68 0.001227
0.013969 11.4 69 0.001245 0.092074 74 70 0.001192 0.074407 62.4 71
0.006233 >0.66 >105.9 72 0.003022 0.052359 17.3 73 0.001697
0.016885 9.9 74 0.00002 0.025249 1262.5 75 0.000125 0.10653 852.2
76 0.000051 0.003288 64.5 78 0.11251 >0.66 >5.9 79 0.00205
0.0972 47.4 85 0.000236 0.011521 48.8 86 0.000212 0.010522 49.6 87
0.000762 0.40679 533.8 88 0.000069 0.004642 67.3 89 0.000129
0.007453 57.8 90 0.002134 0.28384 133 91 0.000193 0.010191 52.8 92
0.004375 0.34857 79.7 93 0.000231 0.013861 60 94 0.00007 0.002317
33.1 95 0.00006 0.015699 261.7 96 0.000047 0.008781 186.8 97
0.000027 0.002611 96.7 98 0.000013 >0.66 >50769.2 99 0.00004
0.00553 138.3 100 0.000116 0.008288 71.4 101 0.000092 0.011152
121.2 102 0.000035 0.002242 64.1 103 0.000056 0.11738 2096.1 104
0.000077 0.049106 637.7 105 0.00008 0.005016 62.7 107 0.002087
0.13041 62.5 108 0.002342 0.059639 25.5 109 0.000161 >0.66
>4099.4 114 0.000096 0.014325 149.2 115 0.000176 0.027527 156.4
116 0.000036 0.008305 230.7 117 0.002299 >0.66 >287.1 118
0.000769 >0.66 >858.3 119 0.000622 0.23029 370.2 120 0.000443
0.099593 224.8 121 0.000001 0.000388 388 122 0.000058 0.012144
209.4 123 0.000015 0.001372 91.5 124 0.000335 0.073725 220.1 125
0.000003 0.011637 3879 126 0.000012 0.1629 13575 127 0.000459
>0.66 >1437.9 128 0.000051 0.363 7117.6 129 0.000056 >0.66
>11785.7 130 0.00014 >0.66 >4714.3 131 0.000106 0.24297
2292.2 132 0.000553 0.31529 570.1 133 0.000009 0.000281 31.2 134
0.000052 0.01805 347.1 135 0.000008 0.006239 779.9 136 0.000259
0.061863 238.9 137 0.000305 0.015977 52.4 138 0.000009 0.005174
574.9 139 0.000101 0.010416 103.1 140 0.004726 >0.66 >139.7
141 0.000673 0.028642 42.6 142 0.003664 0.10184 27.8 143 0.002232
0.075383 33.8 144 0.053902 >0.66 >12.2 145 0.00003 0.012029
401 146 0.044184 >0.66 >14.9 147 0.000514 >0.66 >1284.0
148 0.00289 >0.66 >228.4 149 0.000265 >0.66 >2490.6 150
0.000014 0.009338 667 151 0.000162 >0.66 >4074.1 152 0.000026
0.000412 15.8 153 0.000265 0.093006 351 154 0.000133 0.005375 40.4
155 0.000484 0.037667 77.8 156 0.000116 0.006155 53.1 157 0.004454
>0.66 >148.2 158 0.06478 >0.66 >10.2 161 0.00171
>0.66 >386.0 162 0.001348 0.16692 123.8 163 0.005616 >0.66
>117.5 164 0.000963 0.13795 143.3 165 0.000823 0.036585 44.5 166
0.000459 0.00327 7.1 169 0.00097 0.088637 91.4 170 0.000126
0.003802 30.2 171 0.002942 0.052053 17.7 172 0.002048 0.06569 32.1
173 0.000108 0.022102 204.6 174 0.000105 0.062087 591.3 175 0.0001
>0.660 >6600 176 0.00018 0.032 177.8 177 0.000165 0.132 799.7
178 0.000226 >0.660 >2915.8 179 0.000181 >0.660 >3642.4
180 0.000192 >0.660 >3438.6 181 0.000291 >0.660 >2271.9
182 0.000087 >0.660 >7595.8 183 0.000039 0.009428 240.5 184
0.000281 >0.660 >2345.3 185 0.000228 0.082582 361.5 186
0.00001 0.011199 1069.2 187 0.000329 >0.660 >2003.9 188
0.000102 0.11529 1135.4 189 0.000144 0.051724 358.6 190 0.000512
0.097064 189.6 191 0.000073 0.009162 125.2 194 0.000151 0.032029
212.4 195 0.000039 0.00671 170.2 196 0.000032 >0.660 >20552.4
197 0.000025 0.004837 193 198 0.003966 >0.660 >166.4 199
0.000014 0.005231 369.8 200 0.0001 >0.660 >6588.8 201
0.000125 0.024585 196.6 202 0.000052 0.005073 97.1 203 0.000031
0.004305 139.5 204 0.000145 0.042341 291.3 205 0.000005 0.003573
658.6 206 0.000083 >0.660 >7916.4 207 0.000218 >0.660
>3021.3 208 0.000589 >0.660 >1120.6 209 0.000267 >0.660
>2476.0 210 0.000624 >0.660 >1057.6 211 0.000009 0.005612
651.1 212 0.000737 >0.660 >895.1 213 <0.00001 >0.660
>66000 214 0.000082 0.064044 776.6 215 0.000503 0.060768 120.8
216 0.000615 >0.660 >1073.2 217 0.000262 0.044761 171.1 218
0.000131 0.096873 738.2 219 0.000236 0.029861 126.8 220 0.000192
0.031387 163.7 221 0.000057 0.1701 3005.2 222 0.000107 0.13661
1275.3 223 0.000169 0.097266 574.1 224 <0.00001 0.000999
>99.9 225 0.00001 0.003482 >348.2 226 0.000017 0.009928 577.7
227 0.006831 >0.660 >96.6 228 0.004669 >0.660 >141.4
229 0.049413 >0.660 >13.4 230 0.008819 >0.660 >74.8 231
0.000918 >0.660 >718.8 232 0.00046 0.19749 429.1 233 0.000243
>0.660 >2714.3 234 0.000369 0.024503 66.3 235 0.000252
0.058196 231.4 236 0.000369 >0.660 >1787.6 237 0.000401 0.268
668.3 238 0.00043 >0.660 >1534.3 239 0.000252 0.10842 430.9
240 0.00083 >0.660 >795.4 241 0.006091 >0.660 >108.3
242 0.001796 >0.660 >367.6 243 0.00028 >0.660 >2357.6
244 0.00016 >0.660 >4136.9 245 0.001617 >0.660 >408.2
246 0.000783 0.38418 490.9 247 0.000188 0.027265 145.3 248 0.000013
0.15503 12079.6 249 0.00009 >0.660 >7302.0 250 0.000266
0.21547 811 251 0.000328 0.47166 1438.5 252 0.000077 >0.660
>8570.3 253 0.000142 >0.660 >4663.3 254 0.000126 0.053315
421.7 255 0.007834 >0.660 >84.2 256 0.00012 >0.660
>5519.8 257 0.000171 0.017126 100.2 258 0.000048 0.004085 86 259
0.001995 >0.660 >330.9 260 0.001087 >0.660 >607.2 261
0.000088 >0.660 >7530.1 262 0.003001 >0.660 219.9 263
0.000316 >0.660 >2090.0 264 0.000235 >0.660 >2808.4 265
0.001698 >0.660 >388.8 266 0.000183 >0.660 >3607.7 267
0.000454 >0.660 >1453.3 268 0.000092 0.14465 1563.9 269 nd nd
nd 270 0.003314 >0.660 >199.1 271 0.006156 >0.660
>107.2 272 0.000011 >0.660 >58011.8 273 0.000076 0.18104
2396.1 274 0.000135 0.032908 244.6 275 0.000097 >0.660
>6832.4 276 0.000144 0.38147 2650.8 277 0.029684 >0.660
>22.2 278 0.00071 >0.660 >929.4 279 0.000095 >0.660
>6923.2 280 0.000178 0.19477 1097.2 281 0.000076 0.11925 1558.9
282 0.000164 0.56153 3434.4 283 0.047464 >0.660 >13.9 284
0.001552 >0.660 >425.2
285 0.006994 >0.660 >94.4 286 0.000567 >0.660 >1165.0
287 nd nd nd 288 0.000177 >0.660 >3730.9 289 0.000112
>0.660 >5917.7 290 0.000365 >0.660 >1808.5 291 0.00056
>0.660 >1179.1 292 0.000598 >0.660 >1104.2 293 0.000516
0.2604 505.1 294 0.000258 0.065126 252 295 0.000183 0.10971 599.4
296 0.000651 >0.660 >1014.4 297 0.000128 0.28281 2209.5 298
0.000315 0.44593 1415.7 299 0.000425 0.24551 577.7 300 nd >0.660
nd 301 0.000291 >0.660 >2268.0 302 0.000504 >0.660
>1309.5 303 0.00148 >0.660 >445.9 304 0.000678 >0.660
>973.5 305 0.003684 >0.660 >179.2 306 0.000077 0.047895
622 307 0.003727 >0.660 >177.1 308 0.057376 >0.660
>11.5 309 0.004417 >0.660 >149.4 310 0.000049 >0.660
>13469.4 311 0.00026 >0.660 >2538.5 312 0.00034 >0.660
>1941.2 313 0.000044 0.066 1500 314 0.003066 >0.660 >215.3
315 0.003461 >0.660 >190.7 316 0.000149 0.079528 533.7 317
0.002798 >0.660 >235.9 318 0.001468 0.15067 102.6 319
0.000413 0.20791 503.4 320 0.001243 0.12873 103.6 321 0.000689
>0.660 >957.9 322 0.000184 >0.660 >3591.4 323 0.000949
>0.660 >695.2 324 0.001481 >0.660 >445.7 325 0.002331
>0.660 >283.1 326 0.000116 >0.660 >5708.8 327 0.000031
0.095575 3035.4 328 0.001859 >0.660 >355.0 329 0.000285
>0.660 >2319.5 330 0.074915 >0.660 >8.8 331 0.008266
>0.660 >79.8 332 0.012582 >0.660 >52.5 333 0.000089
>0.660 >7415.7 334 0.000179 >0.660 >3697.5 335 0.000438
>0.660 >1508.2 336 0.000105 0.24152 2301.3 337 0.000535
>0.660 >1233.3 338 0.000403 >0.660 >1637.7 339 0.014136
>0.660 >46.7 340 0.007593 >0.660 >86.9 341 0.012998
>0.660 >50.8 342 0.025752 >0.660 >25.6 343 0.000576
>0.660 >1145.9 344 0.000284 0.44708 1576.9 345 0.001146
>0.660 >575.9 346 0.000018 0.20364 11405.2 347 0.000243
0.30556 1256.7 348 0.000302 0.029266 97.1 349 0.000467 0.024235
51.9 350 0.00597 >0.660 >110.6 351 0.001576 >0.660
>418.7 352 0.006825 >0.660 >96.7 353 0.000292 >0.660
>2260.0 354 0.000036 0.00541 148.8 355 0.00012 >0.660
>5489.5 356 0.005015 >0.660 >131.6 357 0.001336 >0.660
>493.9 358 0.005417 >0.660 >121.8 359 0.013481 >0.660
>49.0 360 0.000228 0.14423 633.9 361 0.007128 >0.660 >92.6
362 0.000082 0.28999 3548.2 363 0.00018 >0.660 >3670.5 364
0.000006 0.07596 12197.3 365 0.001077 >0.660 >612.9 366
0.005457 >0.660 >121.0 367 0.004608 >0.660 >143.2 368
>1.195 >0.660 -- 369 0.8382 >0.660 >0.8 370 0.000904
>0.660 >729.9 371 0.008376 >0.660 >78.8 372 >1.195
>0.660 -- 374 0.002266 >0.660 >291.2 375 0.011254
>0.660 >58.6 376 0.022405 >0.660 >29.5 377 0.00014
0.32457 2317.4 378 0.063003 >0.660 >10.5 379 0.25595
>0.660 >2.6 380 0.000083 0.17491 2107.3 381 0.000054 0.024207
448.3 382 0.00115 >0.660 >573.9 383 0.00217 >0.660
>304.1 384 0.000076 >0.660 >8684.2 385 0.000062 0.12998
2096.5 386 0.000239 0.11818 494.5 387 0.000162 0.27983 1723.4 388
0.000188 0.034845 185.1 389 0.000098 0.067181 685.5 390 0.000341
0.11581 339.6 391 0.00354 >0.660 >186.4 392 0.00038 0.121691
320.2394737 393 0.000083 0.0921 1109.638554 394 0.002507 >660
>263262.863980854 395 0.000798 0.018843 23.62136616 396 0.11567
>660 >5705.88743840235 397 0.022972 >660
>28730.6285913286 398 0.001233 0.083449 67.68513261 399 0.002923
>660 >225764.520763495 400 <0.00001 0.036438 >3643.8
401 <0.00001 0.001621 >162.14 402 0.00003 0.004152
137.4441318 403 0.000003 0.024340 8250.567777 404 0.000012 0.030268
2423.47572 405 0.000040 0.055325 1394.84167 406 0.000035 0.044553
1263.771487 407 0.000015 0.074556 4930.626281 408 0.000002 0.028131
13701.71935 409 <0.000010 0.017485 1748.5 410 0.000055 0.101630
1838.625057 411 0.000003 0.007453 2352.34518 412 0.000021 0.135210
6545.480951 413 0.000120 0.096802 803 .8030391 414 0.000007
0.095640 13930.52218 415 0.000002 0.026900 17326.89211 416 0.000023
0.059112 2568.970013 417 0.000046 0.003986 87.05823249 418 0.000004
0.001566 404.6578954 419 0.000197 0.211240 1070.762368 420 0.000063
0.072108 1153.285139 421 0.000026 0.054039 2089.513572 422 0.000071
0.289500 4073.448713 423 <0.000010 0.007566 756.62 424
<0.000010 0.007825 782.52 425 0.000003 0.003995 1282.243051 426
0.000007 0.004311 604.2384997 427 0.000002 0.085636 34408.55031 428
0.000003 0.015643 5832.15271 429 <0.000010 0.001407 140.65 430
<0.000010 0.000998 99.767 431 <0.000010 0.006774 677.36 432
0.000023 0.009298 408.8250813 433 <0.000010 0.002286 228.55 434
0.000052 0.075474 1459.393611 435 0.000017 0.032896 1935.058824 436
0.000011 0.006500 590.9090909 437 <0.000010 0.000514 51.4 438
<0.000010 0.000345 34.5 439 <0.000010 0.014968 1496.8 440
<0.000010 0.045491 4549.1 441 <0.000010 0.024219 2421.9 442
<0.000010 0.033589 3358.9 443 <0.000010 0.019357 1935.7 444
0.000112 0.081494 727.625 445 0.000028 0.013557 484.1785714 446
0.000038 0.019318 508.3684211 447 0.000028 0.065838 2373.053633 448
0.000005 0.014610 3119.262138 449 0.000240 0.017841 74.40260228 450
0.000299 0.032065 107.2874494 451 <0.000010 0.003599 359.92 452
<0.000010 0.006004 600.39 453 <0.000010 0.003630 363.04 454
0.000026 0.018906 735.2415027 455 0.000004 0.000619 139.3622053 456
<0.000010 0.000540 53.991 457 0.000045 0.330930 7413.638604 458
<0.000010 0.002372 237.24 459 <0.000010 0.005416 541.58 460
0.000049 0.028982 586.5495537 461 0.000093 0.003650 39.43935939 462
0.000026 0.018425 710.8410494 463 0.000007 0.043884 6042.880159 464
0.000081 0.521110 6431.789289 465 0.000025 0.037216 1472.443126 467
0.000080 0.13291 1653.027213 473 0.079276 0.19124 2.412331601 nd =
not determined
TABLE 2 shows the utility of compounds having Formula I to
functionally inhibit anti-apoptotic Bcl-2 protein. It also
surprisingly demonstrates these compounds having comparatively less
affinity for anti-apoptotic Bcl-xL protein, which in turn gives
rise to high binding selectivity ratios (Bcl-xL K.sub.i/Bcl-2
K.sub.i) ranging from >2 to >263, 263. This selectivity for
Bcl-2 protein is significantly greater than compounds previously
disclosed in PCT US 2004/36770 and PCT US 2004/367911, as
exemplified by ABT-737 in TABLE 2.
For some compounds (e.g., 192 and 193), the assay did not detect
any activity against either Bcl-2 or Bcl-XL under the conditions
stated above in the experimental description for the FRET assay. As
those skilled in the art will appreciate, the upper and lower
limits of detection in an assay are influenced by the assay
conditions, and for the FRET assay specifically, by the
concentration of the probe that is used. Since compounds
represented by Examples 192 and 193 show K.sub.i values that are
greater than the limits of detection in the assay format used, it
can be stated that their affinity for Bcl-2 and Bcl-XL is less than
the upper limit of detection of the assays. However, they may still
have affinity for one or both proteins, and the inventors expect
that they also have selectivity for Bcl-2.
Platelet Cell Viability Assay
Platelet-rich plasma (PRP) (prepared in-house according to
conventional techniques) was incubated with ABT-737
(4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(((1R)--
3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfon-
yl)benzamide) or compounds of the invention at various
concentrations for five hours at 37.degree. C. After the
incubation, platelets were equilibrated to room temperature for 20
minutes and then an equal volume of Cell Titer Glo reagent (Promega
Corporation) was added. Samples were mixed for two minutes and then
allowed to equilibrate for an additional 10 minutes at room
temperature. The luminescence generated from the samples was
quantitated using an LJL Analyst plate reader. IC.sub.50 values are
concentrations of compound needed for 50% inhibition of cellular
viability.
FL5.12/Bcl-2 Cell Viability Assay
FL5.12 is an IL-3 dependent prolymphocytic murine cell line that
undergoes apoptosis upon IL-3 withdrawal as a result of the
upregulation of pro-apoptotic Bcl-2 proteins such as Bim and Puma.
Stable overexpression of anti-apoptotic Bcl-2 protein
(FL5.12/Bcl-2) protects against apoptosis induced by IL-3
withdrawal by sequestration of Bim and Puma. [Refs. Harada, et. al.
PNAS 101, 15313 (2004); Certo, et. al. Cancer Cell 9, 351 (2006).]
The ability of compounds to kill FL5.12/Bcl-2 cells upon IL-3
withdrawal is a direct measure of the compounds' ability to inhibit
anti-apoptotic Bcl-2 protein function.
Wild type FL5.12/Bcl-2 overexpressing stable transfectants were
cultured in RPMI-1640 supplemented with 2 mM L-glutamine, 10% FBS,
1 mM sodium pyruvate, 2 mM HEPES, 1% penicillin/streptomycin
(Invitrogen), 57 .mu.M (3-ME, and 10% WEHI-3B conditioned medium
(source of IL-3) and maintained at 37.degree. C. containing 5%
CO.sub.2. 1.times.10.sup.6 cells/ml were washed 1.times.PBS and
resuspended in medium not supplemented with 10% WEHI-3B for 48 hrs
prior to cytotoxicity assays. Cells were then treated for an
additional 24 hrs in the presence of various concentrations of the
indicated compounds. Cell viability was assessed by CellTitre Glo
assay (Promega Corp.) according to the manufacturer's
recommendations.
Data analysis was performed using GraphPad Prism 4.0 and results
are shown in TABLE 3 below.
TABLE-US-00003 TABLE 3 Cellular Activity Selectivity Canine Ratio
FL5.12/ platelets (Platelet EC.sub.50/ Bcl-2 EC.sub.50 FL5.12/Bcl-2
EC.sub.50 (.mu.M) (.mu.M) EC.sub.50) ABT- 0.025 0.282 11 737 18
0.123 29.69 241 21 1.01 >50 >49 22 0.825 >50 >61 23
1.44 >50 >35 24 0.055 >50 >906 25 0.049 >50 >1020
26 0.035 >50 >1429 40 0.165 >50 >303 45 0.139 >50
>360 46 0.041 30 725 52 0.016 >50 >3164 53 0.011 18.325
1697 54 0.064 >50 >785 55 0.022 36 1614 56 0.049 27 554 57
0.016 16.8 1077 68 0.044 >50 >1144 69 0.075 >50 >666 70
0.111 >50 >450 71 0.46 >50 >107 72 0.154 >50 >325
73 0.14 23.22 166 74 0.008 16.71 1989 75 0.022 17.73 821 76 0.039
8.66 221 86 0.074 36.27 489 88 0.032 19.87 613 89 0.065 31.95 495
94 0.04 23.85 590 96 0.011 22.27 2043 97 0.013 14.1 1052 98 0.004
17.94 4849 99 0.009 21.72 2440 100 0.015 31.25 2029 102 0.02 20.21
996 103 0.014 31.35 2305 104 0.021 >50 >2392 105 0.013 30.31
2262 106 0.009 15.24 1657 109 0.036 >50 >1404 120 0.319
>50 >157 121 0.038 0.309 8 122 0.04 >50 >1259 123 0.087
2.81 32 125 0.01 44.83 4719 126 0.031 >50 >1618 128 0.025
>50 >2000 129 0.021 >50 >2415 130 0.197 >50 >254
131 0.031 >50 >1597 132 0.042 >50 >1196 133 0.02 0.095
5 134 0.048 4.72 98 135 0.042 4.55 108 136 0.19 >50 >263 137
0.281 >50 >178 138 0.029 17.75 616 139 0.046 38.5 841 140
2.13 >50 >23 141 0.076 >50 >661 142 0.27 >50 >185
143 0.199 >50 >251 144 0.046 40.02 864 145 0.004 3.21 730 146
0.152 21.97 145 147 0.009 17.62 1895 148 0.071 19.77 278 149 0.013
16.74 1298 150 0.006 2.9 509 151 0.049 31.4 642 152 0.009 2.66 283
154 0.085 29 343 155 0.421 >50 >119 166 0.153 >50 >327
170 0.015 7.35 507 171 0.276 >50 >181 172 0.194 >50
>257 173 0.011 >50 >4587 174 0.011 19.5 1857 175 0.0062 nd
nd 176 0.0585 nd nd 177 0.01966 nd nd 178 0.0186 nd nd 179 0.02346
nd nd 180 0.02047 nd nd 181 0.03353 nd nd 182 0.01242 nd nd 183
0.03077 nd nd 184 0.02698 nd nd 185 0.06335 nd nd 186 0.02036 nd nd
187 0.34128 nd nd 188 0.02466 nd nd 189 0.01489 nd nd 190 0.02421
nd nd 191 0.01172 nd nd 192 >0.5 nd nd 193 >0.5 nd nd 194
0.02697 nd nd 195 0.01124 nd nd 196 0.01236 nd nd 197 0.00618 nd nd
198 nd nd nd 199 0.02854 nd nd 200 0.00629 nd nd 201 0.0174 nd nd
202 0.01383 nd nd 203 0.0223 nd nd 204 0.02738 nd nd 205 0.03753 nd
nd 206 0.00501 nd nd 207 0.1199 nd nd 208 0.26403 nd nd 209 0.13896
nd nd 210 0.25691 nd nd 211 0.01713 nd nd 212 >0.5 nd nd 213
0.43216 nd nd 214 0.01569 nd nd 215 0.11576 nd nd 216 0.03985 nd nd
217 0.02083 nd nd 218 0.033 nd nd 219 0.02296 nd nd 220 0.02403 nd
nd 221 0.14872 nd nd 222 0.02366 nd nd 223 0.03713 nd nd 224
0.02116 nd nd 225 0.02989 nd nd 226 0.02301 nd nd 227 >0.5 nd nd
228 >0.5 nd nd 229 >0.5 nd nd 230 0.17755 nd nd 231 0.0509 nd
nd 232 0.01228 nd nd 233 nd nd nd 234 nd nd nd 235 nd nd nd 236 nd
nd nd 237 nd nd nd 238 0.05896 nd nd 239 0.01764 nd nd 240 0.20943
nd nd 241 nd nd nd 242 0.16457 nd nd 243 0.028 nd nd 244 0.02025 nd
nd 245 0.07244 nd nd 246 0.048 nd nd 247 0.01607 nd nd 248 0.04981
nd nd 249 0.0412 nd nd 250 0.07951 nd nd 251 0.07812 nd nd 252
0.00662 nd nd 253 0.00758 nd nd 254 0.01693 nd nd 255 >0.5 nd nd
256 0.00889 nd nd 257 0.00934 nd nd 258 0.00911 nd nd 259 >0.5
nd nd 260 0.05944 nd nd 261 0.01701 nd nd 262 0.17622 nd nd 263
0.02835 nd nd 264 0.02571 nd nd 265 0.24417 nd nd 266 0.01148 nd nd
267 0.05643 nd nd 268 0.06822 nd nd 269 nd nd nd 270 0.42893 nd nd
271 >0.5 nd nd 272 0.19406 nd nd 273 0.07001 nd nd 274 0.15519
nd nd 275 0.03801 nd nd 276 0.06218 nd nd 277 >0.5 nd nd 278
0.15272 nd nd 279 0.01623 nd nd 280 0.24715 nd nd 281 0.06022 nd nd
282 0.09216 nd nd 283 >0.5 nd nd 284 >0.5 nd nd 285 >0.5
nd nd 286 0.27896 nd nd 287 nd nd nd 288 0.06432 nd nd 289 0.02736
nd nd 290 0.04468 nd nd 291 0.05801 nd nd 292 0.06916 nd nd 293
0.06806 nd nd 294 0.05981 nd nd 295 0.04634 nd nd 296 0.18237 nd nd
297 0.01321 nd nd 298 0.01948 nd nd 299 0.07725 nd nd 300 0.06215
nd nd 301 0.05945 nd nd 302 0.03238 nd nd 303 >0.5 nd nd 304
0.41529 nd nd 305 >0.5 nd nd 306 0.00716 nd nd 307 >0.5 nd nd
308 >0.5 nd nd 309 >0.5 nd nd 310 0.00451 nd nd 311 0.0334 nd
nd 312 0.01924 nd nd 313 0.08289 nd nd 314 0.24014 nd nd 315
>0.5 nd nd 316 0.06749 nd nd 317 0.08309 nd nd 318 0.07695 nd nd
319 0.03141 nd nd 320 0.04158 nd nd 321 0.02909 nd nd 322 0.04445
nd nd 323 0.09208 nd nd 324 0.13417 nd nd 325 0.25639 nd nd 326
0.03509 nd nd 327 0.00657 nd nd 328 >0.5 nd nd 329 0.12652 nd nd
330 >0.5 nd nd 331 >0.5 nd nd 332 >0.5 nd nd 333 0.10932
nd nd 334 0.06592 nd nd
335 0.03897 nd nd 336 0.00749 nd nd 337 0.12389 nd nd 338 0.07113
nd nd 339 >0.5 nd nd 340 >0.5 nd nd 341 >0.5 nd nd 342
>0.5 nd nd 343 0.05489 nd nd 344 0.07147 nd nd 345 >0.5 nd nd
346 0.01747 nd nd 347 0.04681 nd nd 348 0.0872 nd nd 349 0.14571 nd
nd 350 0.31119 nd nd 351 0.34452 nd nd 352 0.15632 nd nd 353
0.05828 nd nd 354 0.0056 nd nd 355 >0.5 nd nd 356 >0.5 nd nd
357 >0.5 nd nd 358 >0.5 nd nd 359 >0.5 nd nd 360 0.10622
nd nd 361 >0.5 nd nd 362 0.17126 nd nd 363 0.08692 nd nd 364
0.18474 nd nd 365 >0.5 nd nd 366 >0.5 nd nd 367 >0.5 nd nd
368 >0.5 nd nd 369 >0.5 nd nd 370 0.26334 nd nd 371 >0.5
nd nd 372 >0.5 nd nd 374 >0.5 nd nd 375 >0.5 nd nd 376
>0.5 nd nd 377 0.08573 nd nd 378 >0.5 nd nd 379 >0.5 nd nd
380 0.06849 nd nd 381 0.07185 nd nd 382 >0.5 nd nd 383 >0.5
nd nd 384 0.10121 nd nd 385 0.05636 nd nd 386 0.15353 nd nd 387
0.08652 nd nd 388 0.08288 nd nd 389 0.02812 nd nd 390 0.04118 nd nd
391 >0.5 nd nd 392 nd nd nd 393 nd nd nd 394 nd nd nd 395 nd nd
nd 396 >0.5 nd nd 397 nd nd nd 398 0.33382 nd nd 399 >0.5 nd
nd 400 0.00847 nd nd 401 0.00538 nd nd 402 0.01336 nd nd 403
0.00292 nd nd 404 0.00234 nd nd 405 0.01162 nd nd 406 0.02046 nd nd
407 0.0081 nd nd 408 0.00239 nd nd 409 0.0012 nd nd 410 0.01386 nd
nd 411 0.01145 nd nd 412 0.00948 nd nd nd = not determined
TABLE 3 shows the utility of compounds having Formula I to
functionally inhibit anti-apoptotic Bcl-2 protein in a cellular
context. FL5.12 is an IL-3 dependent prolymphocytic murine cell
line that undergoes apoptosis upon IL-3 withdrawal as a result of
the upregulation of pro-apoptotic Bcl-2 family proteins such as Bim
and Puma. Stable overexpression of anti-apoptotic Bcl-2 protein
(FL5.12/Bcl-2) protects against apoptosis induced by IL-3
withdrawal by sequestration of Bim and Puma. (Refs. Harada, et. al.
PNAS 2004, 101, 15313; Certo, et. al. Cancer Cell 2006, 9, 351.)
The ability of compounds to kill FL5.12/Bcl-2 cells upon IL-3
withdrawal is a direct measure of the compounds ability to inhibit
anti-apoptotic Bcl-2 protein function. Compounds of Formula I are
very effective in killing FL5.12/Bcl-2 cells under IL-3 withdrawal
as demonstrated by low EC.sub.50 values.
Compounds of this invention bind to anti-apoptotic Bcl-2 proteins
with high affinity and potently inhibit the function of
anti-apoptotic Bcl-2 protein in a cellular context and are
therefore expected to have utility in treatment of diseases during
which anti-apoptotic Bcl-2 protein is expressed.
The anti-apoptotic Bcl-xL protein has been disclosed elsewhere
(Cell Mar. 23, 2007, 128, 1173-1176.) to be the major regulator of
the survival of circulating platelets in animals. Genetic mutations
to Bcl-xL protein that decrease Bcl-xL protein stability and
half-life causes a decrease in platelet survival and life-span in
mice bearing these mutations. A potent pharmacologic inhibitor of
Bcl-xL, ABT-737, causes a rapid, concentration dependant decrease
in circulating platelets following injection into C57BL/6 mice or
in beagle canines (Cell Mar. 23, 2007, 128, 1173-1176.; Cell Death
Differ. May 2007; 14(5), 943-51). Thus, without being limited by
theory, compounds of this invention that have reduced affinity for
Bcl-xL can be expected to show lower levels of platelet apoptosis
than previously reported compounds with higher Bcl-xL affinity.
The effect of compounds on platelet survival can be directly
evaluated ex vivo by examining the viability of isolated canine
platelets in the presence of various concentrations of compound.
The data in Table 3 shows that compounds of Formula I have
significantly less to no effect on the viability of isolated canine
platelets ex vivo (higher EC.sub.50 values) compared to compounds
previously disclosed in PCT US 2004/36770 and PCT US 2004/367911,
as exemplified by ABT-737. Furthermore, the functional selectivity
ratio (canine platelet EC.sub.50: FL5.12/Bcl-2 EC.sub.50) for
compounds of Formula I ranges from 32 to 4849, which is
significantly higher than that for compounds previously disclosed
in PCT US 2004/36770 and PCT US 2004/367911, as exemplified by
ABT-737.
Because compounds having Formula I bind to anti-apoptotic Bcl-2
protein with comparatively lower binding to anti-apoptotic
Bcl-X.sub.L protein, the compounds would have utility as
medicaments for the treatment of cancer and autoimmune and immune
diseases with reduction of the side effect of thrombocytopenia
(i.e., they would be circulating platelet-sparing). Involvement of
Bcl-X.sub.L in thrombocytopenia is disclosed in Cell Mar. 23, 2007,
128, 1173-1176. As described herein and elsewhere, a potent
inhibitor of Bcl-X.sub.L, ABT-737, causes a dose-dependent decrease
in circulating platelets following injection into C57BL/6 mice or
in canines (Cell Death Differ. May 2007; 14(5), 943-51). Compounds
with reduced Bcl-X.sub.L affinity exhibit substantially less to no
decrease in circulating platelets. Thus, without being limited by
theory, compounds of this invention that have reduced affinity for
Bcl-X.sub.1, can be expected to show lower levels of platelet
apoptosis than previously reported compounds with higher
Bcl-X.sub.L affinity. The EC.sub.50 data in TABLE 2 show the
effects of administration of compounds of this invention, compared
to ABT-737, on canine platelets.
Involvement of Bcl-2 protein in bladder cancer, brain cancer,
breast cancer, bone marrow cancer, cervical cancer, chronic
lymphocytic leukemia, colorectal cancer, esophageal cancer,
hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,
lymphoid malignancies of T-cell or B-cell origin, melanoma,
myelogenous leukemia, myeloma, oral cancer, ovarian cancer,
non-small cell lung cancer, prostate cancer, small cell lung
cancer, chronic lymphocytic leukemia, myeloma, prostate cancer
spleen cancer, and the like is described in commonly-owned PCT US
2004/36770, published as WO 2005/049593, and PCT US 2004/37911,
published as WO 2005/024636.
Involvement of Bcl-2 proteins in immune and autoimmune diseases is
described in Current Allergy and Asthma Reports 2003, 3, 378-384;
British Journal of Haematology 2000, 110(3), 584-90; Blood 2000,
95(4), 1283-92; and New England Journal of Medicine 2004, 351(14),
1409-1418.
Involvement of Bcl-2 protein in arthritis is disclosed in
commonly-owned U.S. Provisional Patent Application Ser. No.
60/988,479.
Involvement of Bcl-2 protein in bone marrow transplant rejection is
disclosed in commonly-owned U.S. patent application Ser. No.
11/941,196 (now U.S. Published Application 20080182845A1).
Overexpression of Bcl-2 protein correlates with resistance to
chemotherapy, clinical outcome, disease progression, overall
prognosis or a combination thereof in various cancers and disorders
of the immune system. Cancers include, but are not limited to,
hematologic and solid tumor types such as acoustic neuroma, acute
leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia
(monocytic, myeloblastic, adenocarcinoma, angiosarcoma,
astrocytoma, myelomonocytic and promyelocytic), acute t-cell
leukemia, basal cell carcinoma, bile duct carcinoma, bladder
cancer, brain cancer, breast cancer (including estrogen-receptor
positive breast cancer), bronchogenic carcinoma, Burkitt's
lymphoma, cervical cancer, chondrosarcoma, chordoma,
choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia,
chronic myelocytic (granulocytic) leukemia, chronic myelogenous
leukemia, colon cancer, colorectal cancer, craniopharyngioma,
cystadenocarcinoma, dysproliferative changes (dysplasias and
metaplasias), embryonal carcinoma, endometrial cancer,
endotheliosarcoma, ependymoma, epithelial carcinoma,
erythroleukemia, esophageal cancer, estrogen-receptor positive
breast cancer, essential thrombocythemia, Ewing's tumor,
fibrosarcoma, gastric carcinoma, germ cell testicular cancer,
gestational trophoblastic disease, glioblastoma, head and neck
cancer, heavy chain disease, hemangioblastoma, hepatoma,
hepatocellular cancer, hormone insensitive prostate cancer,
leiomyosarcoma, liposarcoma, lung cancer (including small cell lung
cancer and non-small cell lung cancer),
lymphangioendothelio-sarcoma, lymphangiosarcoma, lymphoblastic
leukemia, lymphoma (lymphoma, including diffuse large B-cell
lymphoma, follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's
lymphoma), malignancies and hyperproliferative disorders of the
bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and
uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia,
medullary carcinoma, medulloblastoma, melanoma, meningioma,
mesothelioma, multiple myeloma, myelogenous leukemia, myeloma,
myxosarcoma, neuroblastoma, oligodendroglioma, oral cancer,
osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary
adenocarcinomas, papillary carcinoma, peripheral T-cell lymphoma,
pinealoma, polycythemia vera, prostate cancer (including
hormone-insensitive (refractory) prostate cancer), rectal cancer,
renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma,
sebaceous gland carcinoma, seminoma, skin cancer, small cell lung
carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer,
squamous cell carcinoma, synovioma, sweat gland carcinoma,
testicular cancer (including germ cell testicular cancer), thyroid
cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine
cancer, Wilms' tumor and the like.
It is also expected that compounds having Formula I would inhibit
growth of cells expressing Bcl-2 protein derived from a pediatric
cancer or neoplasm including embryonal rhabdomyosarcoma, pediatric
acute lymphoblastic leukemia, pediatric acute myelogenous leukemia,
pediatric alveolar rhabdomyosarcoma, pediatric anaplastic
ependymoma, pediatric anaplastic large cell lymphoma, pediatric
anaplastic medulloblastoma, pediatric atypical teratoid/rhabdoid
tumor of the central nervous system, pediatric biphenotypic acute
leukemia, pediatric Burkitts lymphoma, pediatric cancers of Ewing's
family of tumors such as primitive neuroectodermal rumors,
pediatric diffuse anaplastic Wilm's tumor, pediatric favorable
histology Wilm's tumor, pediatric glioblastoma, pediatric
medulloblastoma, pediatric neuroblastoma, pediatric
neuroblastoma-derived myelocytomatosis, pediatric pre-B-cell
cancers (such as leukemia), pediatric psteosarcoma, pediatric
rhabdoid kidney tumor, pediatric rhabdomyosarcoma, and pediatric
T-cell cancers such as lymphoma and skin cancer and the like.
Autoimmune disorders include acquired immunodeficiency disease
syndrome (AIDS), autoimmune lymphoproliferative syndrome, hemolytic
anemia, inflammatory diseases, and thrombocytopenia, acute or
chronic immune disease associated with organ transplantation,
Addison's disease, allergic diseases, alopecia, alopecia areata,
atheromatous disease/arteriosclerosis, atherosclerosis, arthritis
(including osteoarthritis, juvenile chronic arthritis, septic
arthritis, Lyme arthritis, psoriatic arthritis and reactive
arthritis), autoimmune bullous disease, abetalipoprotemia, acquired
immunodeficiency-related diseases, acute immune disease associated
with organ transplantation, acquired acrocyanosis, acute and
chronic parasitic or infectious processes, acute pancreatitis,
acute renal failure, acute rheumatic fever, acute transverse
myelitis, adenocarcinomas, aerial ectopic beats, adult (acute)
respiratory distress syndrome, AIDS dementia complex, alcoholic
cirrhosis, alcohol-induced liver injury, alcohol-induced hepatitis,
allergic conjunctivitis, allergic contact dermatitis, allergic
rhinitis, allergy and asthma, allograft rejection,
alpha-1-antitrypsin deficiency, Alzheimer's disease, amyotrophic
lateral sclerosis, anemia, angina pectoris, ankylosing spondylitis
associated lung disease, anterior horn cell degeneration, antibody
mediated cytotoxicity, antiphospholipid syndrome, anti-receptor
hypersensitivity reactions, aortic and peripheral aneurysms, aortic
dissection, arterial hypertension, arteriosclerosis, arteriovenous
fistula, arthropathy, asthenia, asthma, ataxia, atopic allergy,
atrial fibrillation (sustained or paroxysmal), atrial flutter,
atrioventricular block, atrophic autoimmune hypothyroidism,
autoimmune haemolytic anaemia, autoimmune hepatitis, type-1
autoimmune hepatitis (classical autoimmune or lupoid hepatitis),
autoimmune mediated hypoglycaemia, autoimmune neutropaenia,
autoimmune thrombocytopaenia, autoimmune thyroid disease, B cell
lymphoma, bone graft rejection, bone marrow transplant (BMT)
rejection, bronchiolitis obliterans, bundle branch block, burns,
cachexia, cardiac arrhythmias, cardiac stun syndrome, cardiac
tumors, cardiomyopathy, cardiopulmonary bypass inflammation
response, cartilage transplant rejection, cerebellar cortical
degenerations, cerebellar disorders, chaotic or multifocal atrial
tachycardia, chemotherapy associated disorders, chlamydia,
choleosatatis, chronic alcoholism, chronic active hepatitis,
chronic fatigue syndrome, chronic immune disease associated with
organ transplantation, chronic eosinophilic pneumonia, chronic
inflammatory pathologies, chronic mucocutaneous candidiasis,
chronic obstructive pulmonary disease (COPD), chronic salicylate
intoxication, colorectal common varied immunodeficiency (common
variable hypogammaglobulinaemia), conjunctivitis, connective tissue
disease associated interstitial lung disease, contact dermatitis,
Coombs positive haemolytic anaemia, cor pulmonale,
Creutzfeldt-Jakob disease, cryptogenic autoimmune hepatitis,
cryptogenic fibrosing alveolitis, culture negative sepsis, cystic
fibrosis, cytokine therapy associated disorders, Crohn's disease,
dementia pugilistica, demyelinating diseases, dengue hemorrhagic
fever, dermatitis, dermatitis scleroderma, dermatologic conditions,
dermatomyositis/polymyositis associated lung disease, diabetes,
diabetic arteriosclerotic disease, diabetes mellitus, Diffuse Lewy
body disease, dilated cardiomyopathy, dilated congestive
cardiomyopathy, discoid lupus erythematosus, disorders of the basal
ganglia, disseminated intravascular coagulation, Down's Syndrome in
middle age, drug-induced interstitial lung disease, drug-induced
hepatitis, drug-induced movement disorders induced by drugs which
block CNS dopamine, receptors, drug sensitivity, eczema,
encephalomyelitis, endocarditis, endocrinopathy, enteropathic
synovitis, epiglottitis, Epstein-Barr virus infection,
erythromelalgia, extrapyramidal and cerebellar disorders, familial
hematophagocytic lymphohistiocytosis, fetal thymus implant
rejection, Friedreich's ataxia, functional peripheral arterial
disorders, female infertility, fibrosis, fibrotic lung disease,
fungal sepsis, gas gangrene, gastric ulcer, giant cell arteritis,
glomerular nephritis, glomerulonephritides, Goodpasture's syndrome,
goitrous autoimmune hypothyroidism (Hashimoto's disease), gouty
arthritis, graft rejection of any organ or tissue, graft versus
host disease, gram negative sepsis, gram positive sepsis,
granulomas due to intracellular organisms, group B streptococci
(GBS) infection, Grave's disease, haemosiderosis associated lung
disease, hairy cell leukemia, hairy cell leukemia,
Hallerrorden-Spatz disease, Hashimoto's thyroiditis, hay fever,
heart transplant rejection, hemachromatosis, hematopoietic
malignancies (leukemia and lymphoma), hemolytic anemia, hemolytic
uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage,
Henoch-Schoenlein purpurea, Hepatitis A, Hepatitis B, Hepatitis C,
HIV infection/HIV neuropathy, Hodgkin's disease,
hypoparathyroidism, Huntington's chorea, hyperkinetic movement
disorders, hypersensitivity reactions, hypersensitivity
pneumonitis, hyperthyroidism, hypokinetic movement disorders,
hypothalamic-pituitary-adrenal axis evaluation, idiopathic
Addison's disease, idiopathic leucopaenia, idiopathic pulmonary
fibrosis, idiopathic thrombocytopaenia, idiosyncratic liver
disease, infantile spinal muscular atrophy, infectious diseases,
inflammation of the aorta, inflammatory bowel disease, insulin
dependent diabetes mellitus, interstitial pneumonitis,
iridocyclitis/uveitis/optic neuritis, ischemia-reperfusion injury,
ischemic stroke, juvenile pernicious anaemia, juvenile rheumatoid
arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma,
Kawasaki's disease, kidney transplant rejection, legionella,
leishmaniasis, leprosy, lesions of the corticospinal system, linear
IgA disease, lipidema, liver transplant rejection, Lyme disease,
lymphederma, lymphocytic infiltrative lung disease, malaria, male
infertility idiopathic or NOS, malignant histiocytosis, malignant
melanoma, meningitis, meningococcemia, microscopic vasculitis of
the kidneys, migraine headache, mitochondrial multi-system
disorder, mixed connective tissue disease, mixed connective tissue
disease associated lung disease, monoclonal gammopathy, multiple
myeloma, multiple systems degenerations (Mencel Dejerine-Thomas
Shi-Drager and Machado-Joseph), myalgic encephalitis/Royal Free
Disease, myasthenia gravis, microscopic vasculitis of the kidneys,
mycobacterium avium intracellulare, mycobacterium tuberculosis,
myelodyplastic syndrome, myocardial infarction, myocardial ischemic
disorders, nasopharyngeal carcinoma, neonatal chronic lung disease,
nephritis, nephrosis, nephrotic syndrome, neurodegenerative
diseases, neurogenic I muscular atrophies, neutropenic fever,
Non-alcoholic Steatohepatitis, occlusion of the abdominal aorta and
its branches, occlusive arterial disorders, organ transplant
rejection, orchitis/epidydimitis, orchitis/vasectomy reversal
procedures, organomegaly, osteoarthrosis, osteoporosis, ovarian
failure, pancreas transplant rejection, parasitic diseases,
parathyroid transplant rejection, Parkinson's disease, pelvic
inflammatory disease, pemphigus vulgaris, pemphigus foliaceus,
pemphigoid, perennial rhinitis, pericardial disease, peripheral
atherlosclerotic disease, peripheral vascular disorders,
peritonitis, pernicious anemia, phacogenic uveitis, pneumocystis
carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy,
organomegaly, endocrinopathy, monoclonal gammopathy, and skin
changes syndrome), post perfusion syndrome, post pump syndrome,
post-MI cardiotomy syndrome, postinfectious interstitial lung
disease, premature ovarian failure, primary biliary cirrhosis,
primary sclerosing hepatitis, primary myxoedema, primary pulmonary
hypertension, primary sclerosing cholangitis, primary vasculitis,
Progressive supranucleo Palsy, psoriasis, psoriasis type 1,
psoriasis type 2, psoriatic arthropathy, pulmonary hypertension
secondary to connective tissue disease, pulmonary manifestation of
polyarteritis nodosa, post-inflammatory interstitial lung disease,
radiation fibrosis, radiation therapy, Raynaud's phenomenon and
disease, Refsum's disease, regular narrow QRS tachycardia, Reiter's
disease, renal disease NOS, renovascular hypertension, reperfusion
injury, restrictive cardiomyopathy, rheumatoid arthritis associated
interstitial lung disease, rheumatoid spondylitis, sarcoidosis,
Schmidt's syndrome, scleroderma, senile chorea, Senile Dementia of
Lewy body type, sepsis syndrome, septic shock, seronegative
arthropathies, shock, sickle cell anemia, Sjigren's disease
associated lung disease, Sjorgren's syndrome, skin allograft
rejection, skin changes syndrome, small bowel transplant rejection,
sperm autoimmunity, multiple sclerosis (all subtypes), spinal
ataxia, spinocerebellar degenerations, spondyloarthropathy,
sporadic, polyglandular deficiency type I sporadic, polyglandular
deficiency type II, Still's disease, streptococcal myositis,
stroke, structural lesions of the cerebellum, Subacute sclerosing
panencephalitis, sympathetic ophthalmia, Syncope, syphilis of the
cardiovascular system, systemic anaphylaxis, systemic inflammatory
response syndrome, systemic onset juvenile rheumatoid arthritis,
systemic lupus erythematosus, systemic lupus
erythematosus-associated lung disease, systemic sclerosis, systemic
sclerosis-associated interstitial lung disease, T-cell or FAB ALL,
Takayasu's disease/arteritis, Telangiectasia, Th2 Type and Th1 Type
mediated diseases, thromboangitis obliterans, thrombocytopenia,
thyroiditis, toxicity, toxic shock syndrome, transplants,
trauma/hemorrhage, type-2 autoimmune hepatitis (anti-LKM antibody
hepatitis), type B insulin resistance with acanthosis nigricans,
type III hypersensitivity reactions, type IV hypersensitivity,
ulcerative colitic arthropathy, ulcerative colitis, unstable
angina, uremia, urosepsis, urticaria, uveitis, valvular heart
diseases, varicose veins, vasculitis, vasculitic diffuse lung
disease, venous diseases, venous thrombosis, ventricular
fibrillation, vitiligo acute liver disease, viral and fungal
infections, vital encephalitis/aseptic meningitis, vital-associated
hemaphagocytic syndrome, Wegener's granulomatosis,
Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection
of any organ or tissue, yersinia and salmonella-associated
arthropathy and the like.
Schemes and Experimentals
The following schemes are presented to provide what is believed to
be the most useful and readily understood description of procedures
and conceptual aspects of this invention. Compounds of this
invention may be made by synthetic chemical processes, examples of
which are shown herein. It is meant to be understood that the order
of the steps in the processes may be varied, that reagents,
solvents and reaction conditions may be substituted for those
specifically mentioned, and that vulnerable moieties may be
protected and deprotected, as necessary.
The following abbreviations have the meanings indicated. ADDP means
1,1'-(azodicarbonyl)dipiperidine; AD-mix-3 means a mixture of
(DHQD).sub.2PHAL, K.sub.3Fe(CN).sub.6, K.sub.2CO.sub.3, and
K.sub.2SO.sub.4); 9-BBN means 9-borabicyclo(3.3.1)nonane; Boc means
tert-butoxycarbonyl; (DHQD).sub.2PHAL means hydroquinidine
1,4-phthalazinediyl diethyl ether; DBU means
1,8-diazabicyclo(5.4.0)undec-7-ene; DIBAL means diisobutylaluminum
hydride; DIEA means diisopropylethylamine; DMAP means
N,N-dimethylaminopyridine; DMF means N,N-dimethylformamide; dmpe
means 1,2-bis(dimethylphosphino)ethane; DMSO means DMSO; dppb means
1,4-bis(diphenylphosphino)-butane; dppe means
1,2-bis(diphenylphosphino)ethane; dppf means
1,1'-bis(diphenylphosphino)ferrocene; dppm means
1,1-bis(diphenylphosphino)methane; EDAC.HCl means
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Fmoc
means fluorenylmethoxycarbonyl; HATU means
O-(7-azabenzotriazol-1-yl)-N,N'N'N'-tetramethyluronium
hexafluorophosphate; HMPA means hexamethylphosphoramide; IPA means
isopropyl alcohol; MP-BH.sub.3 means macroporous triethylammonium
methylpolystyrene cyanoborohydride; TEA means triethylamine; TFA
means trifluoroacetic acid; THF means tetrahydrofuran; NCS means
N-chlorosuccinimide; NMM means N-methylmorpholine; NMP means
N-methylpyrrolidine; PPh.sub.3 means triphenylphosphine.
##STR00014##
Compounds of Formula (4) can be prepared as shown in SCHEME 1, and
can be used as described in SCHEME 7 to prepare compounds of
Formula (I), which are representative of the compounds of the
present invention. Compounds of Formula (I) wherein R is alkyl,
R.sup.100 is as described for substituents on R.sup.26, and n is 1,
2, or 3; can be converted to compounds of Formula (2) using
R.sup.37CH.sup.2MgX.sup.1, wherein X.sup.1 is a halide, in a
solvent such as but not limited to ether or tetrahydrofuran.
Compounds of Formula (3) can be prepared from compounds of Formula
(2) using a strong base such as NaH and R.sup.50X.sup.2, wherein
X.sup.2 is a halide and R.sup.50a is as described herein. Compounds
of Formula (3), when treated with aqueous NaOH or LiOH, will
provide compounds of Formula (4).
##STR00015##
As shown in SCHEME 2, compounds of Formula (5) can be reacted with
compounds of Formula (6) and a reducing agent to provide compounds
of Formula (7). Examples of reducing agents include sodium
borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride,
polymer supported cyanoborohydride, and the like. The reaction is
typically performed in a solvent such as but not limited to
methanol, tetrahydrofuran, and dichloromethane or mixtures thereof.
Compounds of Formula (8) can be prepared from compounds of Formula
(7) as described in SCHEME 1, and can be used as described in
SCHEME 7 to prepare compounds of Formula (I).
##STR00016##
Compounds of Formula (9), when reacted with a compound a Formula
(10) wherein X is a halide or triflate, and a base will provide a
compound of Formula (11). Bases useful in the reaction include
triethylamine, diisopropylethylamine and the like. Compounds of
Formula (13), wherein R.sup.41 is as described herein for
substituents on R.sup.37, can be prepared from compounds of Formula
(11) and compounds of Formula (12) using Suzuki coupling conditions
known to those skilled in the art and readily available in the
literature. Compounds of Formula (14) can be prepared from
compounds of Formula (13) as described in SCHEME 1, and can be used
as described in SCHEME 7 to prepare compounds of Formula (I).
##STR00017## As shown in SCHEME 4, compounds of Formula (17) can be
prepared from compounds of Formula (15) and compounds of Formula
(16), wherein R is alkyl and R.sup.41 is as described herein, using
Suzuki coupling conditions known to those skilled in the art and
readily available in the literature. Compounds of Formula (17) can
be reduced to compounds of Formula (18) using a reducing agent such
as LiAlH.sub.4 in a solvent such as but not limited to diethyl
ether or THF. Compounds of Formula (19) can be prepared from
compounds of Formula (18) using Dess-Martin periodinane or Swern
oxidation conditions known to those skilled in the art and readily
available in the literature. Compounds of Formula (19) can be
reacted with a compound of Formula (5) and a reducing agent to
provide compounds of Formula (20). Examples of reducing agents
include sodium borohydride, sodium cyanoborohydride, sodium
triacetoxyborohydride, polymer supported cyanoborohydride, and the
like. The reaction is typically performed in a solvent such as but
not limited to methanol, tetrahydrofuran, 1,2-dichloroethane, and
dichloromethane or mixtures thereof. Compounds of Formula (21) can
be prepared from compounds of Formula (20) as described in SCHEME
1, and can be used as described in SCHEME 7 to prepare compounds of
Formula (I).
##STR00018##
As shown in SCHEME 5, compounds of Formula (22), wherein R is
alkyl, may be converted to compounds of Formula (23) by reacting
the former, wherein X.sup.1 is Cl, Br, I, or CF.sub.3SO.sub.3--,
and compounds of Formula R.sup.50A--OH and a catalyst, with or
without a first base. Examples of catalysts include copper(I)
trifluoromethanesulfonate toluene complex, PdCl.sub.2,
Pd(OAc).sub.2, and Pd.sub.2(dba).sub.3. Examples of first bases
include triethylamine, N,N-diisopropylethylamine, Cs.sub.2CO.sub.3,
Na.sub.2CO.sub.3, K.sub.3PO.sub.4, and mixtures thereof.
Compounds of Formula (22) may also be converted to compounds of
Formula (23) by reacting the former, when X.sup.1 is Cl, F, or
NO.sub.2, and compounds of Formula R.sup.50A--OH with a first base.
Examples of first bases include triethylamine,
N,N-diisopropylethylamine, Cs.sub.2CO.sub.3, Na.sub.2CO.sub.3,
K.sub.3PO.sub.4, and mixtures thereof.
##STR00019##
Compounds of Formula (18) can be reacted with mesyl chloride and a
base such as but not limited to triethylamine, followed by
N-t-butoxycarbonylpiperazine, to provide compounds of Formula (24).
Compounds of Formula (25) can be prepared by reacting compounds of
Formula (24) with triethylsilane and trifluoroacetic acid.
Compounds of Formula (25) can be reacted with compounds of Formula
(26) and HK.sub.2PO.sub.4 to provide compounds of Formula (27) in a
solvent such as but not limited to dimethylsulfoxide. Compounds of
Formula (28) can be prepared from compounds of Formula (27) as
described in SCHEME 1, and can be used as described in SCHEME 7 to
prepare compounds of Formula (I).
##STR00020## As shown in SCHEME 7, compounds of Formula (32), which
can be prepared as described herein, may be converted to compounds
of Formula (33) by reacting the former with ammonia. Compounds of
Formula (33) may be converted to compounds of Formula (I) by
reacting the former and compounds of Formula (4), (8), (14), (21),
(23), (28), or (38) and a coupling agent, with or without a first
base. Examples of coupling agents include
1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride,
1,1'-carbonyldiimidazole, and
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.
Examples of first bases include triethylamine,
N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixtures
thereof.
##STR00021##
Compounds of Formula (33), prepared as described in SCHEME 7, can
also be converted to compounds of Formula (I) by reacting the
former and compounds of Formula (34) and a first base. Examples of
first bases include but are not limited to sodium hydride,
triethylamine, N,N-diisopropylethylamine,
4-(dimethylamino)pyridine, and mixtures thereof.
##STR00022##
As shown in SCHEME 9, compounds of Formula (35), wherein L is a
bond, alkyl, O, S, S(O), S(O).sub.2, NH, etc., can be reacted with
compounds of Formula (36), to provide compounds of Formula (37).
The reaction is typically performed at elevated temperatures in a
solvent such as but not limited to dimethylsulfoxide, and may
require the use of a base such as but not limited to potassium
phosphate, potassium carbonate, and the like. Compounds of Formula
(38) can be prepared from compounds of Formula (37) as described in
SCHEME 1, and can be used as described in SCHEME 7 to prepare
compounds of Formula (I).
##STR00023##
Compounds of Formula (39), wherein Y is as described herein for
substituents on R.sup.37, can be prepared from compounds of Formula
(39A) wherein X is a halide or triflate, and Y--B(OH).sub.2 using
Suzuki coupling conditions known to those skilled in the art and
readily available in the literature. Compounds of Formula (39) can
be reacted with tert-butyl piperazine-1-carboxylate and a reducing
agent such as sodium triacetoxyborohydride to provide compounds of
Formula (40). The reaction is typically performed in a solvent such
as but not limited to methylene chloride. Compounds of Formula (41)
can be prepared from compounds of Formula (40) by reacting the
latter with R.sup.50X, wherein X is a halide, and NaH in a solvent
such as N,N-dimethylformamide, and then the resulting material can
be treated with triethylsilane and trifluoroacetic acid in
dichloromethane. Compounds of Formula (41) can be used as described
in Scheme 9 wherein CH.sub.2R.sup.37 is as shown in Formula
(41).
##STR00024##
As shown in SCHEME 11, substituted piperazin-2-ones wherein
R.sup.50 is alkyl, can be reacted with compounds of Formula (6a)
and a reducing agent such as sodium triacetoxyborohydride in
dichloromethane to provide compounds of Formula (42). Compounds of
Formula (42) can be reduced to compounds of Formula (43) using a
reducing agent such as but not limited to lithium aluminum hydride
in a solvent such as but not limited to tetrahydrofuran. Compounds
of Formula (43) can be used as described in Scheme 9 wherein
CH.sub.2R.sup.37 is as shown in Formula (43).
The following examples are presented to provide what is believed to
be the most useful and readily understood description of procedures
and conceptual aspects of this invention. The exemplified compounds
were named using ACD/ChemSketch Version 5.06 (5 Jun. 2001, Advanced
Chemistry Development Inc., Toronto, Ontario), or ChemDraw.RTM.
Ver. 9.0.5 (CambridgeSoft, Cambridge, Mass.). Intermediates were
named using ChemDraw.RTM. Ver. 9.0.5 (CambridgeSoft, Cambridge,
Mass.).
Example 1
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide
Example 1A
tert-butyl
4-((4'-chlorobiphenyl-2-yl)methyl)piperazine-1-carboxylate
4'-Chlorobiphenyl-2-carbaldehyde (EXAMPLE 27C) (4.1 g), tert-butyl
piperazine-1-carboxylate (4.23 g), and sodium triacetoxyborohydride
(5.61 g) in CH.sub.2Cl.sub.2 (60 mL) were combined stirred for 24
hours. The reaction was quenched with methanol and poured into
ether. The solution was washed with water and brine, concentrated,
and chromatographed on silica gel with 2-25% ethyl
acetate/hexanes.
Example 1B
1-((4'-chlorobiphenyl-2-yl)methyl)piperazine
EXAMPLE 1A (3.0 g) and triethylsilane (1 mL) were stirred in
CH.sub.2Cl.sub.2 (30 mL) and trifluoroacetic acid (30 mL) for 2
hours, and the reaction was concentrated, and then taken up in
ether and concentrated again. The product was used without further
purification.
Example 1C
methyl 4-fluoro-2-phenoxybenzoate
Methyl 2-bromo-4-fluorobenzoate (1 g), phenol (0.565 g), cesium
carbonate (1.96 g), copper(I) triflate toluene complex (0.087 g),
and ethyl acetate (0.034 mL) in toluene (12 mL) was stirred at
110.degree. C. for 24 hours. The reaction was cooled and
chromatographed on silica gel with 5% ethyl acetate/hexanes.
Example 1D
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzo-
ate
EXAMPLE 1C (630 mg), EXAMPLE 1B, and K.sub.2CO.sub.3 (707 mg) were
stirred in dimethylsulfoxide at 125.degree. C. for 5 hours. The
reaction was cooled and chromatographed on silica gel with 10%
ethyl acetate/hexanes.
Example 1E
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoic
acid
EXAMPLE 1D (600 mg) was stirred in 25 mL 2:1 dioxane/1M NaOH at
60.degree. C. for 24 hours. The solution was cooled and adjusted to
pH 4 with NaH.sub.2PO.sub.4 solution and concentrated HCl, and
extracted with ethyl acetate. The extract was washed with brine and
dried (Na.sub.2SO.sub.4), filtered and concentrated.
Example 1F
3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide
4-Fluoro-3-nitrobenzenesulfonamide (2.18 g),
(tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g)
were stirred in tetrahydrofuran (30 mL) for 24 hours. The solution
was diluted with ethyl acetate, washed with NaH.sub.2PO.sub.4
solution and brine, and dried (Na.sub.2SO.sub.4), filtered and
concentrated. The product was triturated from ethyl acetate.
Example 1G
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide
EXAMPLE 1E (90 mg), EXAMPLE 1F (45 mg),
1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (65
mg), and 4-dimethylaminopyridine (22 mg) were stirred in
CH.sub.2Cl.sub.2 (4 mL) for 24 hours. The reaction was cooled and
chromatographed on silica gel with 20-100% ethyl acetate/hexanes.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.55
(brs, 1H), 8.63 (t, 1H), 8.47 (d, 1H), 7.75 (d, 1H), 7.46 (m, 6H),
7.35 (m, 2H), 7.24 (m, 3H), 7.15 (d, 1H), 6.99 (dd, 1H), 6.82 (d,
2H), 6.75 (d, 1H), 6.38 (d, 1H), 3.86 (br d, 2H), 3.49 (m, 2H),
3.37 (br s, 2H), 3.15 (br s, 4H), 2.34 (br s, 4H), 1.91 (hr s, 4H),
1.64 (hr d, 2H) 1.29 (m, 3H).
Example 2
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-phenoxy-N-({4-
-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
Example 2A
4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide
4-Aminobenzenesulfonamide (6.80 g),
tetrahydropyran-4-carboxaldehyde (4.96 g), and sodium
triacetoxyborohydride (16.74 g) in tetrahydrofuran (300 mL) and
acetic acid (15 mL) were stirred in for 24 hours. The reaction was
concentrated and taken up in ethyl acetate. The resulting solution
was washed with water and brine, concentrated, and chromatographed
on silica gel with 50% ethyl acetate/hexanes.
Example 2B
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-phenoxy-N-({4-
-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 2A for EXAMPLE 1F
in EXAMPLE 1G. .sup.1H NMR (500 MHz, dimethylsulfoxide-ddD.sub.2O)
.delta. 7.54 (d, 1H), 7.46 (m, 8H), 7.36 (m, 4H), 7.24 (d, 1H),
7.13 (dd, 1H), 6.93 (d, 2H), 6.75 (d, 1H), 6.55 (d, 2H), 6.30 (d,
1H), 3.86 (dd, 2H), 3.36 (s, 2H), 3.28 (t, 2H), 3.10 (br s, 4H),
2.96 (d, 2H), 2.32 (br s, 4H), 1.76 (m, 1H), 1.64 (d, 2H), 1.20 (m,
2H).
Example 3
2-(benzyloxy)-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-
-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzam-
ide
Example 3A
methyl 2-(benzyloxy)-4-fluorobenzoate
Methyl 4-fluoro-2-hydroxybenzoate (2.00 g), benzyl bromide (1.54
mL), and cesium carbonate (4.60 g) in N,N-dimethylformamide (50 mL)
were stirred for 24 hours. The reaction was taken up in ether and
washed with 3.times.1M NaOH solution, and brine, then concentrated
to give the pure product.
Example 3B
methyl
2-(benzyloxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)b-
enzoate
This example was prepared by substituting EXAMPLE 3A for EXAMPLE 1C
in EXAMPLE 1D.
Example 3C
2-(benzyloxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoic
acid
This example was prepared by substituting EXAMPLE 3B for EXAMPLE 1D
in EXAMPLE 1E.
Example 3D
2-(benzyloxy)-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-
-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzam-
ide
This example was prepared by substituting EXAMPLE 3C for EXAMPLE 1E
in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 10.90 (br s, 1H), 8.66 (m, 1H), 8.59 (s, 1H), 7.82 (d, 1H),
7.33-7.55 (m, 12H), 7.18-7.27 (m, 3H), 6.61 (s, 1H), 6.56 (d, 1H),
5.22 (s, 2H), 3.86 (br d, 2H), 3.40 (m, 2H), 3.31 (m, 8H), 2.34 (br
s, 4H), 1.91 (br s, 2H), 1.64 (br d, 2H), 1.29 (m, 3H).
Example 4
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(2-phenylethoxy)b-
enzamide
Example 4A
methyl 4-fluoro-2-phenethoxybenzoate
Methyl 4-fluoro-2-hydroxybenzoate (1.00 g) and phenethyl alcohol
(0.64 mL) were added to triphenylphosphine (1.54 g) and
diisopropylazodicarboxylate (1.04 mL) in tetrahydrofuran (20 mL) at
0.degree. C., and the reaction was stirred at room temperature for
24 hours. The mixture was chromatographed on silica gel with 5%
ethyl acetate/hexanes.
Example 4B
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenethoxybe-
nzoate
This example was prepared by substituting EXAMPLE 4A for EXAMPLE 1C
in EXAMPLE 1D.
Example 4C
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenethoxybenzoic
acid
This example was prepared by substituting EXAMPLE 4B for EXAMPLE 1D
in EXAMPLE 1E.
Example 4D
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(2-phenylethoxy)b-
enzamide
This example was prepared by substituting EXAMPLE 4C for EXAMPLE 1E
in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 10.75 (br s, 1H), 8.66 (m, 2H), 7.91 (d, 1H), 7.47 (m, 6H),
7.20-7.40 (m, 8H), 6.53 (d, 1H), 6.47 (s, 1H), 4.35 (t, 2H), 4.03
(m, 1H), 3.85 (br d, 2H), 3.38 (s, 2H), 3.25 (m, 8H), 3.13 (t, 2H),
2.36 (br s, 4H), 2.21 (br s, 2H), 1.62 (br d, 2H), 1.20 (m, 2H),
1.17 (m, 1H).
Example 5
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(phenylthio)benza-
mide
Example 5A
methyl 4-fluoro-2-(phenylthio)benzoate
5-Fluoro-2-(methoxycarbonyl)phenylboronic acid (1.00 g),
2-(phenylthio)isoindoline-1,3-dione (0.86 g), and
(2-hydroxy-3,5-diisopropylbenzoyloxy)copper (0.29 g) were stirred
in dioxane (15 mL) at 50.degree. C. for 24 hours.
The reaction mixture was chromatographed on silica gel with 5%
ethyl acetate/hexanes.
Example 5B
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylthio)-
benzoate
This example was prepared by substituting EXAMPLE 5A for EXAMPLE 1C
in EXAMPLE 1D.
Example 5C
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylthio)benzoic
acid
This example was prepared by substituting EXAMPLE 5B for EXAMPLE 1D
in EXAMPLE 1E.
Example 5D
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(phenylthio)benza-
mide
This example was prepared by substituting EXAMPLE 5C for EXAMPLE 1E
in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.95 (br s, 1H), 8.59 (m, 2H), 7.93 (d, 1H), 7.63 (d, 1H),
7.15-7.50 (m, 14H), 6.73 (d, 1H), 6.18 (s, 1H), 3.82 (dd, 2H), 3.36
(m, 4H), 3.32 (m, 2H), 2.94 (br s, 4H), 2.30 (br s, 4H), 1.64 (m,
1H), 1.61 (m, 2H), 1.25 (m, 2H).
Example 6
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(phenylthio)--
N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 5C for EXAMPLE 1E
and EXAMPLE 2A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6/D.sub.2O) .delta. 7.65 (d, 2H), 7.55 (d,
1H), 7.33-7.48 (m, 12H), 7.24 (m, 2H), 6.73 (d, 1H), 6.66 (d, 2H),
6.17 (d, 1H), 3.85 (dd, 2H), 3.34 (s, 2H), 3.26 (t, 2H), 2.98 (d,
2H), 2.92 (br s, 4H), 2.25 (br s, 4H), 1.78 (m, 1H), 1.63 (d, 2H),
1.20 (m, 2H).
Example 7
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morph-
olin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(phenylthio)benzamide
Example 7A
4-(3-morpholinopropylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting
3-(N-morpholinyl)-1-propylamine for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 7B
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morph-
olin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(phenylthio)benzamide
This example was prepared by substituting EXAMPLE 5C for EXAMPLE 1E
and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 10.20 (br s, 1H), 8.69 (m, 1H),
8.57 (d, 1H), 7.95 (dd, 2H), 7.71 (m, 1H), 7.31-7.51 (m, 10H),
7.12-7.26 (m, 3H), 6.68 (dd, 1H), 6.07 (m, 1H), 4.06 (s, 2H), 3.68
(m, 4H), 3.50 (m, 2H), 3.32 (m, 6H), 2.88 (m, 4H), 2.27 (m, 4H),
1.91 (m, 2H).
Example 8
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(phenylsulfonyl)b-
enzamide
Example 8A
methyl 4-fluoro-2-(phenylsulfonyl)benzoate
EXAMPLE 5A (0.30 g) and KMnO.sub.4 (1.80 g) were stirred in acetic
acid (40 mL) at 60.degree. C. for 24 hours. The reaction mixture
was filtered through a plug of silica gel, concentrated, and
chromatographed on silica gel with 50% ethyl acetate/hexanes.
Example 8B
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylsulfo-
nyl)benzoate
This example was prepared by substituting EXAMPLE 8A for EXAMPLE 1C
in EXAMPLE 1D.
Example 8C
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylsulfonyl)ben-
zoic acid
This example was prepared by substituting EXAMPLE 8B for EXAMPLE 1D
in EXAMPLE 1E.
Example 8D
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(phenylsulfonyl)b-
enzamide
This example was prepared by substituting EXAMPLE 8C for EXAMPLE 1E
in EXAMPLE 1G. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.95 (br s, 1H), 8.54 (s, 1H), 8.41 (dd, 1H), 7.90 (m,
2H), 7.82 (d, 1H), 7.76 (d, 1H), 7.66 (m, 1H), 7.46 (m, 5H), 7.40
(m, 4H), 7.11 (m, 2H), 6.67 (dd, 1H), 6.62 (m, 1H), 4.36 (m, 1H),
3.82 (dd, 2H), 3.39 (m, 6H), 3.19 (m, 6H), 2.37 (br s, 4H), 1.91
(m, 1H), 1.63 (m, 2H), 1.26 (m, 2H).
Example 9
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(phenylsulfinyl)b-
enzamide
Example 9A
methyl 4-fluoro-2-(phenylsulfinyl)benzoate
OXONE.RTM. (Dupont) (5.60 g) was added portionwise over 1 hour to
EXAMPLE 5A (1.00 g) in a mixture of acetic acid (30 mL), water (30
mL) and CH.sub.2Cl.sub.2 (20 mL), and the reaction was stirred for
an additional 1 hour. The reaction mixture was taken up in ethyl
acetate, washed with Na.sub.2S.sub.2O.sub.3 solution, water, and
brine, concentrated, and chromatographed on silica gel with 5-25%
ethyl acetate/hexanes.
Example 9B
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylsulfi-
nyl)benzoate
This example was prepared by substituting EXAMPLE 9A for EXAMPLE 1C
in EXAMPLE 1D.
Example 9C
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylsulfinyl)ben-
zoic acid
This example was prepared by substituting EXAMPLE 9B for EXAMPLE 1D
in EXAMPLE 1E.
Example 9D
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(phenylsulfinyl)b-
enzamide
This example was prepared by substituting EXAMPLE 9C for EXAMPLE 1E
in EXAMPLE 1G. .sup.1H NMR (500 MHz, dimethylsulfoxide-dd/D.sub.2O)
.delta. 8.51 (s, 1H), 7.85 (dd, 2H), 7.64 (d, 2H), 7.48 (m, 8H),
7.32 (m, 1H), 7.23 (m, 1H), 7.14 (m, 4H), 6.97 (d, 1H), 3.85 (dd,
2H), 3.35 (d, 2H), 3.34 (m, 6H), 3.27 (t, 2H), 2.74 (br s, 4H),
1.93 (m, 1H), 1.64 (d, 2H), 1.28 (m, 2H).
Example 10
2-benzyl-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3--
nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
Example 10A
methyl 2-benzyl-4-fluorobenzoate
5-Fluoro-2-(methoxycarbonyl)phenylboronic acid (1.00 g), benzyl
bromide (0.50 mL), K.sub.2CO.sub.3 (1.75 g), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(PdCl.sub.2(dppf)) (0.17 g) were stirred in tetrahydrofuran (20 mL)
at 60.degree. C. for 24 hours. The reaction mixture was
chromatographed on silica gel with 2% ethyl acetate/hexanes.
Example 10B
methyl
2-benzyl-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoa-
te
This example was prepared by substituting EXAMPLE 10A for EXAMPLE
1C in EXAMPLE 1D.
Example 10C
2-benzyl-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoic
acid
This example was prepared by substituting EXAMPLE 10B for EXAMPLE
1D in EXAMPLE 1E.
Example 10D
2-benzyl-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3--
nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 10C for EXAMPLE
1E in EXAMPLE 1G. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d/D.sub.2O) .delta. 8.55 (d, 1H), 7.90 (d, 1H),
7.38-7.56 (m, 10H), 7.25 (m, 2H), 6.96 (d, 2H), 6.83 (s, 2H), 6.75
(d, 1H), 4.06 (s, 2H), 3.85 (dd, 2H), 3.48 (s, 2H), 3.37 (d, 2H),
3.25 (t, 2H), 3.20 (br s, 4H), 2.44 (br s, 4H), 1.91 (m, 1H), 1.63
(d, 2H), 1.29 (m, 2H).
Example 11
2-benzyl-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4--
[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 10C for EXAMPLE
1E and EXAMPLE 2A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.70 (br s, 1H), 7.48 (m,
6H), 6.88 (m, 6H), 6.62 (m, 6H), 6.42 (dd, 2H), 3.83 (dd, 4H), 3.24
(m, 6H), 2.96 (m, 4H), 1.82 (m, 2H), 1.63 (m, 3H), 1.18 (m,
4H).
Example 12
2-benzyl-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4--
[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 10C for EXAMPLE
1E and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.90 (br s, 1H), 8.80 (m,
1H), 8.54 (d, 1H), 7.91 (dd, 1H), 7.48 (m, 7H), 7.40 (d, 2H), 7.26
(d, 2H), 6.97 (dd, 2H), 6.86 (m, 2H), 6.76 (d, 1H), 4.04 (m, 5H),
3.72 (m, 4H), 3.56 (m, 2H), 3.40 (m, 8H), 3.21 (m, 4H), 2.34 (m,
2H), 1.98 (m, 2H).
Example 13
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(2-phenylethyl)be-
nzamide
Example 13A
methyl 4-fluoro-2-phenethylbenzoate
Methyl 2-bromo-4-fluorobenzoate (1.00 g), (E)-styrylboronic acid
(0.89 g), tetrakis(triphenylphosphine)palladium(O) (0.50 g), and
K.sub.3PO.sub.4 (2.28 g) were stirred in dioxane (17 mL) at
90.degree. C. for 24 hours. The reaction mixture chromatographed on
silica gel with 1-5% ethyl acetate/hexanes. The product in methanol
(10 ml) was added to 20 wt % of fresh dry 5% Pd--C and stirred 4
days with H.sub.2 in a pressure bottle. The mixture was filtered
through a nylon membrane and concentrated.
Example 13B
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenethylben-
zoate
This example was prepared by substituting EXAMPLE 13A for EXAMPLE
1C in EXAMPLE 1D.
Example 13C
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenethylbenzoic
acid
This example was prepared by substituting EXAMPLE 13B for EXAMPLE
1D in EXAMPLE 1E.
Example 13D
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrah-
ydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)-2-phenethylbenzamide
This example was prepared by substituting EXAMPLE 13C for EXAMPLE
1E in EXAMPLE 1G. .sup.1H NMR (500 MHz,
dimethylsulfoxide-ddD.sub.2O) .delta. 8.62 (d, 1H), 7.95 (d, 1H),
7.91 (m, 1H), 7.35-7.52 (m, 6H), 7.19 (m, 2H), 7.13 (m, 2H), 6.99
(m, 4H), 6.83 (d, 1H), 6.70 (d, 1H), 6.65 (s, 1H), 3.80 (m, 2H),
3.24 (m, 2H), 3.18 (t, 2H), 3.11 (br s, 4H), 2.91 (t, 2H), 2.48 (m,
2H), 2.38 (br s, 4H), 1.81 (m, 1H), 1.54 (d, 2H), 1.23 (m, 2H).
Example 14
2-(benzylamino)-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-
-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benz-
amide
Example 14A
methyl 2-(benzylamino)-4-fluorobenzoate
Methyl 2-amino-4-fluorobenzoate (0.90 g), benzaldehyde (0.54 mL),
sodium triacetoxyborohydride (1.58 g) and acetic acid (0.3 mL) in
CH.sub.2Cl.sub.2 (20 mL) were stirred for 3 hours. The reaction was
quenched with methanol, concentrated, and chromatographed on silica
gel with 5% ethyl acetate/hexanes.
Example 14B
methyl
2-(benzylamino)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl-
)benzoate
This example was prepared by substituting EXAMPLE 14A for EXAMPLE
1C in EXAMPLE 1D.
Example 14C
2-(benzylamino)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoi-
c acid
This example was prepared by substituting EXAMPLE 14B for EXAMPLE
1D in EXAMPLE 1E.
Example 14D
2-(benzylamino)-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-
-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benz-
amide
This example was prepared by substituting EXAMPLE 14C for EXAMPLE
1E in EXAMPLE 1G. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6/D.sub.2O) .delta. 8.58 (d, 1H), 7.92 (d,
1H), 7.87 (m, 1H), 7.59 (d, 2H), 7.48 (m, 2H), 7.43 (m, 4H),
7.20-7.29 (m, 8H), 6.15 (d, 1H), 4.32 (s, 2H), 3.85 (m, 2H), 3.49
(m, 2H), 3.33 (m, 2H), 3.26 (t, 2H), 3.12 (br s, 4H), 2.39 (br s,
4H), 1.90 (m, 1H), 1.62 (d, 2H), 1.27 (m, 2H).
Example 15
2-anilino-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-
-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
Example 15A
methyl 4-fluoro-2-(phenylamino)benzoate
Methyl 2-bromo-4-fluorobenzoate (1.00 g), aniline (0.47 mL),
palladium(II) acetate (0.048 g),
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.214 g) and
Cs.sub.2CO.sub.3 (2.08 g) in toluene (12 mL) were stirred at
90.degree. C. for 24 hours. The reaction was concentrated and
chromatographed on silica gel with 5-50% ethyl acetate/hexanes.
Example 15B
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylamino-
)benzoate
This example was prepared by substituting EXAMPLE 15A for EXAMPLE
1C in EXAMPLE 1D.
Example 15C
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylamino)benzoi-
c acid
This example was prepared by substituting EXAMPLE 15B for EXAMPLE
1D in EXAMPLE 1E.
Example 15D
2-anilino-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-
-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 15C for EXAMPLE
1E in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.55 (br s, 1H), 8.56 (m, 2H), 7.92 (d, 1H), 7.72 (d, 1H),
7.47 (m, 6H), 7.25 (m, 4H), 7.12 (d, 2H), 6.95 (m, 2H), 6.53 (s,
1H), 6.38 (dd, 1H), 3.81 (dd, 2H), 3.37 (br s, 4H), 3.12 (br s,
4H), 2.41 (br s, 4H), 1.91 (m, 1H), 1.61 (br d, 2H), 1.23 (m,
4H).
Example 16
2-anilino-4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-
-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 15C for EXAMPLE
1E and EXAMPLE 2A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6/D.sub.2O) .delta. 7.78 (d, 1H), 7.52
(d, 2H), 7.47 (m, 6H), 7.36 (m, 3H), 7.27 (m, 3H), 7.11 (m, 2H),
6.90 (m, 1H), 6.61 (s, 1H), 6.53 (d, 1H), 6.31 (d, 1H), 4.46 (s,
1H), 3.82 (m, 2H), 3.37 (s, 2H), 3.26 (t, 2H), 3.05 (br s, 4H),
2.93 (d, 2H), 2.37 (br s, 4H), 1.77 (m, 1H), 1.63 (d, 2H), 1.20 (m,
2H).
Example 17
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-methoxy-N-({3-
-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
Example 17A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-methoxybenzo-
ate
Methyl 4-bromo-2-methoxybenzoic acid (700 mg), EXAMPLE 1B (983 mg),
K.sub.3PO.sub.4 (909 mg), tris(dibenzylideneacetone)dipalladium(O)
(78 mg), and 2-(di-t-butylphosphino)biphenyl (102 mg) were stirred
in 1,2-dimethoxyethane (10 mL) at 80.degree. C. for 24 hours. The
reaction mixture was chromatographed on silica gel with 20-50%
ethyl acetate/hexanes.
Example 17B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-methoxybenzoic
acid
This example was prepared by substituting EXAMPLE 17A for EXAMPLE
1D in EXAMPLE 1E.
Example 17C
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-methoxy-N-({3-
-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 17B for EXAMPLE
1E in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 10.81 (br s, 1H), 8.64 (m, 2H), 7.96 (d, 1H), 7.20-7.54 (m,
10 OH), 6.52 (d, 1H), 6.46 (s, 1H), 3.90 (s, 3H), 3.40 (m, 4H),
3.27 (br s, 4H), 2.39 (br s, 4H), 1.91 (m, 1H), 1.62 (br d, 2H),
1.27 (m, 4H).
Example 18
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phen-
oxybenzamide
Example 18A
methyl
4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylat-
e
To a suspension of hexane washed NaH (17 g) in dichloromethane (700
mL), 5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) was added
dropwise at 0.degree. C. After stirring for 30 minutes, the mixture
was cooled to -78.degree. C. and trifluoromethanesulfonic anhydride
(40 mL) was added. The reaction mixture was warmed to room
temperature and stirred for 24 hours. The organic layer was washed
with brine, dried, and concentrated to give the product.
Example 18B
methyl 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate
Example 18A (62.15 g), 4-chlorophenylboronic acid (32.24 g), CsF
(64 g and tetrakis(triphenylphosphine)palladium(O) (2 g) in 2:1
1,2-dimethoxyethane/methanol (600 mL) were heated to 70.degree. C.
for 24 hours. The mixture was concentrated. Ether (4.times.200 mL)
was added and the mixture was filtered. The combined ether solution
was concentrated to give the product.
Example 18C
(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol
To a mixture of LiBH.sub.4 (13 g), EXAMPLE 18B (53.8 g) and ether
(400 mL), methanol (25 mL) was added slowly by syringe. The mixture
was stirred at room temperature for 24 hours. The reaction was
quenched with 1N HCl with ice-cooling. The mixture was diluted with
water and extracted by ether (3.times.100 mL). The extracts were
dried, and concentrated. The crude product was chromatographed on
silica gel with 0-30% ethyl acetate/hexanes.
Example 18D
methyl 2-bromo-4-(piperazin-1-yl)benzoate
This example was prepared by substituting piperazine for EXAMPLE 1B
and methyl 2-bromo-4-fluorobenzoate for EXAMPLE 1C in EXAMPLE
1D.
Example 18E
methyl
2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methy-
l)piperazin-1-yl)benzoate
MsCl (7.5 mL) was added via syringe to EXAMPLE 18C (29.3 g) and
triethylamine (30 mL) in CH.sub.2Cl.sub.2 (500 mL) at 0.degree. C.,
and the mixture was stirred for 1 minute. EXAMPLE 18D (25 g) was
added and the reaction was stirred at room temperature for 24
hours. The suspension was washed with brine, dried, and
concentrated. The crude product was chromatographed on silica gel
with 10-20% ethyl acetate/hexanes.
Example 18F
methyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)pipera-
zin-1-yl)-2-phenoxybenzoate
EXAMPLE 18E (500 mg), phenol (195 mg), Cs.sub.2CO.sub.3 (674 mg),
1-naphthoic acid (356 mg), copper (I) triflate-toluene complex (45
mg), ethyl acetate (0.016 mL), and 4A sieves (50 mg) in toluene (2
mL) was stirred at 105.degree. C. for 24 hours. The reaction was
cooled and taken up in ethyl acetate (100 mL) and water (40 mL).
The layers were separated and the organic layer was washed with
2.times.Na.sub.2CO.sub.3 solution and brine, dried, and
concentrated. The crude product was chromatographed on silica gel
with 20% ethyl acetate/hexanes.
Example 18G
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-phenoxybenzoic acid
This example was prepared by substituting EXAMPLE 18F for EXAMPLE
1D in EXAMPLE 1E.
Example 18H
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phen-
oxybenzamide
This example was prepared by substituting EXAMPLE 18G for EXAMPLE
1E and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.10 (br s, 1H), 8.76 (m,
1H), 8.46 (d, 1H), 7.76 (dd, 1H), 7.50 (d, 1H), 7.35 (d, 2H), 7.23
(d, 2H), 7.06 (dd, 2H), 6.99 (dd, 1H), 6.81 (d, 2H), 6.74 (d, 1H),
6.34 (s, 1H), 3.62 (m, 4H), 3.46 (m, 2H), 3.13 (m, 4H), 2.76 (m,
2H), 2.48 (m, 2H), 2.22 (m, 6H), 1.97 (m, 2H), 1.82 (m, 2H), 1.40
(t, 2H), 1.06 (m, 7H), 0.94 (s, 3H).
Example 19
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phen-
oxybenzamide
Example 19A
methyl
5,5-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylat-
e
This example was prepared by substituting
4,4-dimethyl-2-methoxycarbonylcyclohexanone for
5,5-dimethyl-2-methoxycarbonylcyclohexanone in EXAMPLE 18A.
Example 19B
methyl 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enecarboxylate
This example was prepared by substituting EXAMPLE 19A for EXAMPLE
18A in EXAMPLE 18B.
Example 19C
(2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methanol
This example was prepared by substituting EXAMPLE 19B for EXAMPLE
18B in EXAMPLE 18C.
Example 19D
methyl
2-bromo-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methy-
l)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 19C for EXAMPLE
18C in EXAMPLE 18E.
Example 19E
methyl
4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)pipera-
zin-1-yl)-2-phenoxybenzoate
This example was prepared by substituting EXAMPLE 19D for EXAMPLE
18E in EXAMPLE 18F.
Example 19F
4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-phenoxybenzoic acid
This example was prepared by substituting EXAMPLE 19E for EXAMPLE
1D in EXAMPLE 1E.
Example 19G
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phen-
oxybenzamide
This example was prepared by substituting EXAMPLE 19F for EXAMPLE
1E and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.10 (br s, 1H), 8.71 (m,
1H), 8.42 (d, 1H), 7.73 (dd, 1H), 7.53 (d, 1H), 7.34 (d, 2H), 7.21
(dd, 2H), 7.10 (d, 2H), 6.96 (dd, 1H), 6.78 (d, 2H), 6.70 (d, 1H),
6.32 (s, 1H), 3.61 (m, 4H), 3.44 (m, 2H), 3.09 (m, 4H), 2.71 (m,
2H), 2.44 (m, 4H), 2.21 (m, 4H), 1.96 (m, 2H), 1.79 (m, 2H), 1.47
(t, 2H), 1.17 (m, 3H), 1.08 (m, 4H), 0.95 (s, 3H).
Example 20
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indazol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitro-
phenyl}sulfonyl)benzamide
Example 20A
ethyl 2-(1H-indazol-5-yloxy)-4-fluorobenzoate
Ethyl 2,4-difluorobenzoate (1.14 g), K.sub.3PO.sub.4 (1.30 g) and
5-hydroxyindazole (0.90 g) were stirred at 110.degree. C. in
diglyme (12 mL) for 24 hours. The reaction was cooled and poured
into ether. The solution was washed three times with 1M NaOH
solution, and brine, and dried. The solution was then concentrated,
and the crude product was chromatographed on silica gel with 20%
ethyl acetate/hexanes.
Example 20B
tert-butyl
4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piper-
azine-1-carboxylate
This example was prepared by substituting
N-t-butoxycarbonylpiperazine for EXAMPLE 18D in EXAMPLE 18E.
Example 20C
1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine
This EXAMPLE was prepared by substituting EXAMPLE 20B for EXAMPLE
1A in EXAMPLE 1B.
Example 20D
ethyl
2-(1H-indazol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-enyl)methyl)piperazin-1-yl)benzoate
Example 20A
330 mg), EXAMPLE 20C (335 mg), and HK.sub.2PO.sub.4 (191 mg
were stirred in dimethylsulfoxide (5 mL) at 140.degree. C. for 24
hours. The reaction was diluted with ethyl acetate, washed three
times with water, washed with brine, dried, and concentrated. The
crude product was chromatographed on silica gel with 30% ethyl
acetate/hexanes.
Example 20E
2-(1H-indazol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-
yl)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 20D for EXAMPLE
1D in EXAMPLE 1E.
Example 20F
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indazol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitro-
phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 20E for EXAMPLE
1E and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 13.03 (br s, 1H), 11.25 (br
s, 1H), 8.70 (m, 1H), 8.48 (d, 1H), 7.94 (dd, 1H), 7.68 (dd, 1H),
7.52 (m, 2H), 7.34 (d, 2H), 7.06 (m, 4H), 6.96 (dd, 1H), 6.88 (d,
1H), 6.23 (s, 1H), 3.61 (m, 4H), 3.44 (m, 2H), 3.05 (m, 4H), 2.73
(m, 2H), 2.42 (m, 4H), 2.18 (m, 4H), 1.99 (m, 2H), 1.91 (d, 2H),
1.78 (m, 2H), 1.39 (t, 2H), 1.17 (m, 2H), 0.93 (s, 6H).
Example 21
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indazol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitro-
phenyl}sulfonyl)benzamide
Example 21A
4-(1-methylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting
4-amino-N-methylpiperidine for (tetrahydropyran-4-yl)methylamine in
EXAMPLE 1F.
Example 21B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indazol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitro-
phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 20E for EXAMPLE
1E and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 12.80 (br s, 1H), 10.70 (br
s, 1H), 8.34 (s, 1H), 8.02 (d, 1H), 7.87 (d, 1H), 7.70 (dd, 1H),
7.55 (m, 2H), 7.36 (d, 2H), 7.06 (m, 2H), 6.95 (m, 1H), 6.72 (d,
1H), 6.62 (d, 1H), 6.24 (s, 1H), 3.35 (m, 4H), 3.18 (m, 2H), 3.00
(m, 2H), 2.80 (m, 4H), 2.73 (m, 2H), 2.20 (m, 4H), 1.99 (m, 2H),
1.91 (s, 3H), 1.54 (m, 1H), 1.41 (t, 2H), 1.22 (m, 2H), 1.09 (s,
6H).
Example 22
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1,2-
,3,4-tetrahydroquinolin-6-yloxy)benzamide
Example 22A
ethyl 4-fluoro-2-(1,2,3,4-tetrahydroquinolin-6-yloxy)benzoate
This example was prepared by substituting
5-hydroxy-1,2,3,4-tetrahydroquinoline for 5-hydroxyindazole in
EXAMPLE 20A.
Example 22B
ethyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperaz-
in-1-yl)-2-(1,2,3,4-tetrahydroquinolin-6-yloxy)benzoate
This example was prepared by substituting EXAMPLE 22A for EXAMPLE
20A in EXAMPLE 20D.
Example 22C
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(1,2,3,4-tetrahydroquinolin-6-yloxy)benzoic acid
This example was prepared by substituting EXAMPLE 22B for EXAMPLE
1D in EXAMPLE 1E.
Example 22D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1,2-
,3,4-tetrahydroquinolin-6-yloxy)benzamide
This example was prepared by substituting EXAMPLE 22C for EXAMPLE
1E and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 10.95 (br s, 1H), 8.83 (m,
1H), 8.60 (d, 1H), 7.90 (dd, 1H), 7.46 (d, 1H), 7.35 (d, 2H), 7.21
(dd, 2H), 7.06 (d, 2H), 6.62 (m, 2H), 6.42 (d, 1H), 6.11 (d, 1H),
5.61 (br s, 1H), 4.02 (m, 1H), 3.61 (m, 4H), 3.48 (m, 2H), 3.17 (m,
2H), 3.07 (m, 4H), 2.74 (m, 2H), 2.63 (m, 2H), 2.44 (m, 4H), 2.19
(m, 4H), 1.97 (m, 4H), 1.79 (m, 4H), 1.41 (t, 2H), 1.17 (m, 4H),
0.94 (s, 6H).
Example 23
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1,2-
,3,4-tetrahydroquinolin-6-yloxy)benzamide
This example was prepared by substituting EXAMPLE 22C for EXAMPLE
1E and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.10 (br s, 1H), 8.71 (m,
1H), 8.42 (d, 1H), 7.73 (dd, 1H), 7.53 (d, 1H), 7.34 (d, 2H), 7.21
(dd, 2H), 7.10 (d, 2H), 6.96 (dd, 1H), 6.78 (d, 2H), 6.70 (d, 1H),
6.32 (s, 1H), 3.61 (m, 4H), 3.44 (m, 2H), 3.09 (m, 4H), 2.71 (m,
2H), 2.44 (m, 4H), 2.21 (m, 4H), 1.96 (m, 2H), 1.79 (m, 2H), 1.47
(t, 2H), 1.17 (m, 3H), 1.08 (m, 4H), 0.95 (s, 3H).
Example 24
4-(4-{[4'-chloro-4-(pyrrolidin-1-ylmethyl)-1,1'-biphenyl-2-yl]methyl}piper-
azin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylme-
thyl)amino]phenyl}sulfonyl)benzamide
Example 24A
methyl 5-formyl-2-(trifluoromethylsulfonyloxy)benzoate
Triflic anhydride (7.74 mL) was added to methyl
5-formyl-2-hydroxybenzoate (7.5 g) in 150 mL CH.sub.2Cl.sub.2 at
0.degree. C., and the reaction was stirred and allowed to warm to
room temperature over 3 hours. The reaction was diluted with
CH.sub.2Cl.sub.2 (150 mL), washed with 3.times. brine, dried over
Na.sub.2SO.sub.4, and concentrated. The product was used without
further purification.
Example 24B
methyl 4'-chloro-4-formylbiphenyl-2-carboxylate
EXAMPLE 24A (14.5 g), 4-chlorophenylboronic acid (6.88 g) CsF (12.2
g), and tetrakis(triphenylphosphine)palladium(O) were stirred at
70.degree. C. for 24 hours. The reaction was cooled, filtered, and
concentrated. The crude product was taken up in ethyl acetate (250
mL), washed with 3.times.1M NaOH, and brine, concentrated, and
chromatographed on silica gel with 10% ethyl acetate/hexanes.
Example 24C
methyl
4'-chloro-4-(pyrrolidin-1-ylmethyl)biphenyl-2-carboxylate
This example was prepared by substituting EXAMPLE 24B for
4'-chlorobiphenyl-2-carboxaldehyde and pyrrolidine for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 24D
(4'-chloro-4-(pyrrolidin-1-ylmethyl)biphenyl-2-yl)methanol
DIBAL in hexanes (1M, 5.9 mL) was added to EXAMPLE 24C (650 mg) in
CH.sub.2Cl.sub.2 (30 mL) at 0.degree. C., and the reaction was
stirred for 20 minutes. The reaction was quenched by the slow
addition of methanol (2 mL), and 1M NaOH (10 mL), and the resulting
solution was extracted twice with ethyl acetate. The extracts were
washed with brine, dried over Na.sub.2SO.sub.4, and concentrated.
The product was used without further purification.
Example 24E
4'-chloro-4-(pyrrolidin-1-ylmethyl)biphenyl-2-carbaldehyde
Dess-Martin periodinane (1.30 g) was added to EXAMPLE 24D (770 mg)
in CH.sub.2Cl.sub.2 (30 mL) at room temperature and the reaction
was stirred for 24 hours. The reaction mixture was concentrated and
chromatographed on silica gel with 1% triethylamine in 25% ethyl
acetate/hexanes.
Example 24F
methyl 2-(1H-indol-4-yloxy)-4-fluorobenzoate
This example was prepared by substituting 4-hydroxyindole for
5-hydroxyindazole and methyl 2,4-difluorobenzoate for ethyl
2,4-difluorobenzoate in EXAMPLE 20A.
Example 24G
tert-butyl
4-(3-(1H-indol-4-yloxy)-4-(methoxycarbonyl)phenyl)piperazine-1--
carboxylate
This example was prepared by substituting EXAMPLE 24F for EXAMPLE
20A and tert-butyl piperazine-1-carboxylate for EXAMPLE 20C in
EXAMPLE 20D.
Example 24H
methyl 2-(1H-indol-4-yloxy)-4-(piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 24G for EXAMPLE
1A in EXAMPLE 1B.
Example 24I
methyl
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-4-(pyrrolidin-1-ylmethyl)biph-
enyl-2-yl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 24E for
4'-chlorobiphenyl-2 carboxaldehyde and EXAMPLE 24H for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 24J
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-4-(pyrrolidin
1-ylmethyl)biphenyl-2-yl)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 241 for EXAMPLE
1D in EXAMPLE 1E.
Example 24K
4-(4-{[4'-chloro-4-(pyrrolidin-1-ylmethyl)-1,1'-biphenyl-2-yl]methyl}piper-
azin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylme-
thyl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 24J for EXAMPLE
1E in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.52 (br s, 1H), 11.26 (s, 1H), 10.68 (br s, 1H), 8.61
(dd, 1H), 8.49 (s, 1H), 8.19 (br s, 1H), 7.66 (d, 2H), 7.54 (m,
3H), 7.36 (m, 2H), 7.28 (s, 1H), 7.24 (d, 1H), 7.05 (d, 1H), 6.95
(dd, 1H), 6.75 (d, 1H), 6.35 (m, 2H), 6.26 (s, 1H), 4.38 (m, 3H),
3.85 (dd, 2H), 3.61 (m, 4H), 3.24 (m, 4H), 3.09 (m, 4H), 2.85 (m,
2H), 2.35 (m, 2H), 2.02 (m, 2H), 1.87 (m, 4H), 1.60 (m, 2H), 1.25
(m, 2H).
Example 25
4-(4-{[4'-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1'-biphenyl-2-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylm-
ethyl)amino]phenyl}sulfonyl)benzamide
Example 25A
methyl 4'-chloro-4-(2-oxoethyl)biphenyl-2-carboxylate
To a solution of (methoxymethyl)diphenylphosphine oxide (1.62 g) in
40 mL tetrahydrofuran at -78.degree. C., was added lithium
diisopropylamide (2M, 3.3 mL), and after stirring 3 minutes,
EXAMPLE 24B (1.57 g) was added, and the solution was warmed to room
temperature. NaH (230 mg), and 40 mL N,N-dimethylformamide were
added, and the mixture was heated to 60.degree. C. for 1 hours. The
reaction was cooled and poured into NaH.sub.2PO.sub.4 solution. The
resulting solution was extracted twice with ether, and the combined
extracts were washed twice with water, and brine, and concentrated.
The crude mixture of enol ethers was taken up in 1M HCl (50 mL) and
dioxane (50 mL), and stirred at 60.degree. C. for 3 hours. The
reaction was cooled and poured into NaHCO.sub.3 solution. The
resulting solution was extracted twice with ether, and the combined
extracts were washed with water, and brine, and concentrated. The
product was used without further purification.
Example 25B
methyl
4'-chloro-4-(2-(pyrrolidin-1-yl)ethyl)biphenyl-2-carboxylate
This example was prepared by substituting EXAMPLE 25A for
4'-chlorobiphenyl-2-carboxaldehyde and pyrrolidine for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 25C
(4'-chloro-4-(2-(pyrrolidin-1-yl)ethyl)biphenyl-2-yl)methanol
This example was prepared by substituting EXAMPLE 25B for EXAMPLE
24C in EXAMPLE 24D.
Example 25D
4'-chloro-4-(2-(pyrrolidin-1-yl)ethyl)biphenyl-2-carbaldehyde
This example was prepared by substituting EXAMPLE 25C for EXAMPLE
24D in EXAMPLE 24E.
Example 25E
methyl
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-4-(2-(pyrrolidin-1-yl)ethyl)b-
iphenyl-2-yl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 25D for
4'-chlorobiphenyl-2 carboxaldehyde and EXAMPLE 24H for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 25F
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-4-(2-(pyrrolidin
1-yl)ethyl)biphenyl-2-yl)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 25E for EXAMPLE
1D in EXAMPLE 1E.
Example 25G
4-(4-{[4'-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1'-biphenyl-2-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylm-
ethyl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 25F for EXAMPLE
1E in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.15 (s, 1H), 8.47 (t, 1H), 8.42 (s, 1H), 7.68 (dd, 1H),
7.58 (d, 1H), 7.44 (m, 4H), 7.22 (m, 3H), 7.10 (d, 1H), 6.92 (m,
2H), 6.68 (d, 1H), 6.34 (d, 1H), 6.26 (s, 2H), 3.87 (dd, 2H), 3.61
(m, 4H), 3.10-3.24 (m, 11H), 2.97 (m, 4H), 2.31 (m, 4H), 1.89 (m,
4H), 1.61 (m, 2H), 1.26 (m, 2H).
Example 26
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-
-(1H-indol-5-yloxy)benzamide
Example 26A
ethyl 2-(1H-indol-5-yloxy)-4-fluorobenzoate
This example was prepared by substituting 5-hydroxyindole for
5-hydroxyindazole in EXAMPLE 20A.
Example 26B
ethyl
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex--
1-enyl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 26A for EXAMPLE
20A in EXAMPLE 20D.
Example 26C
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl-
)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 26B for EXAMPLE
1D in EXAMPLE 1E.
Example 26D
4-(1-cyclopentylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting
1-cyclopentylpiperidin-4-amine for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 26E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-
-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 26D for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.13 (br s, 1H), 8.52 (s,
1H), 8.14 (d, 1H), 7.80 (d, 1H), 7.52 (d, 1H), 7.35 (m, 4H), 7.04
(m, 4H), 6.80 (d, 1H), 6.61 (d, 1H), 6.36 (s, 1H), 6.14 (s, 1H),
5.76 (s, 1H), 3.84 (m, 2H), 3.24 (m, 4H), 2.99 (m, 4H), 2.85 (m,
2H), 2.71 (m, 2H), 2.16 (m, 6H), 1.95 (m, 4H), 1.50-1.70 (m, 6H),
1.38 (m, 2H), 1.17 (m, 2H), 0.93 (s, 6H).
Example 27
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]-3-isobutylpiperazin-1-yl}-N-({-
3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenox-
ybenzamide
Example 27A
methyl 2-bromo-4-methylpentanoate
To concentrated HBr (48%) (20 mL) in water (214 mL), was added KBr
(17.6 g, cooled to 0.degree. C., then sodium nitrite (5.2 g) all at
once, then DL-leucine (5.2 g) in a few portions. The reaction was
mechanically stirred at 0.degree. C. for 1.5 hours, then extracted
with 2.times.200 mL ethyl acetate. The combined organic layers were
washed with brine and dried over Na.sub.2SO.sub.4. After filtration
and concentration, the resultant oil was dissolved in
CH.sub.2Cl.sub.2/methanol and treated with 2.0M (TMS)CHN.sub.2 in
ether (30 mL) at room temperature for 10 minutes. The reaction was
concentrated and then purified by flash chromatography using
97.5/2.5 hexane/ethyl acetate.
Example 27B
3-isobutylpiperazin-2-one
EXAMPLE 27A (2.2 g) in ethanol (15 mL) was added dropwise over a
period of 2.5 hours to a stirred refluxing solution of
ethane-1,2-diamine (13.2 mL) in ethanol (60 mL). Heating was
continued for another 2.5 hours, then NaOEt in ethanol was added
(21% by wt, 4.0 mL) and heated for another 90 minutes. The reaction
was then cooled and concentrated. After trituration with ether, the
title compound was used without purification.
Example 27C
4'-chlorobiphenyl-2-carbaldehyde
To 2-bromobenzaldehyde (2.3 ml) and
tetrakis(triphenylphosphine)palladium(O) (0.35 g) in toluene (50
mL), was added 4-chlorophenylboronic acid (4.0 g) and 2M
Na.sub.2CO.sub.3 (70 ml). The mixture was heated under reflux for
one hour. The reaction was cooled, diluted with water and extracted
with ethyl acetate. The organic layer was washed with brine and the
combined aqueous layers back-extracted with ethyl acetate. The
combined organic layers were dried over Na.sub.2SO.sub.4. The crude
material was purified by flash chromatography using 97.5/2.5
hexane/ethyl acetate.
Example 27D
4-((4'-chlorobiphenyl-2-yl)methyl)-3-isobutylpiperazin-2-one
This example was prepared by substituting EXAMPLE 27B for
tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
Example 27E
1-((4'-chlorobiphenyl-2-yl)methyl)-2-isobutylpiperazine
To a solution of EXAMPLE 27D in tetrahydrofuran (3.6 mL) was added
borane-methyl sulfide complex (10M in tetrahydrofuran) (0.24 mL).
The reaction was heated under reflux for 16 hours, then cooled in
an ice/water bath. Methanol (5 mL) was added carefully, and the
mixture was stirred cold for 75 minutes. Then 4N HCl in dioxane
(0.65 mL) was added and the reaction heated under reflux for 60
minutes. After cooling to room temperature, 1N NH.sub.4OH (2.6 mL)
was added and the reaction was stirred for 15 minutes. Then the
reaction was concentrated, redissolved in methanol, concentrated,
redissolved in toluene and concentrated. The crude solids were
slurried in CHCl.sub.3/methanol, the solids were filtered off, and
the filtrate concentrated to afford the title compound.
Example 27F
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)-3-isobutylpiperazin-1-yl)-2-p-
henoxybenzoate
This example was prepared by substituting EXAMPLE 27E for EXAMPLE
1B in EXAMPLE 1D.
Example 27G
4-(4-((4'-chlorobiphenyl-2-yl)methyl)-3-isobutylpiperazin-1-yl)-2-phenoxyb-
enzoic acid
This example was prepared by substituting EXAMPLE 27F for EXAMPLE
1D in EXAMPLE 1E.
Example 27H
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]-3-isobutylpiperazin-1-yl}-N-({-
3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenox-
ybenzamide
EXAMPLE 27G (13 mg), EXAMPLE 1F (7 mg),
1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (8
mg), and 4-dimethylaminopyridine (5 mg) were stirred in
CH.sub.2Cl.sub.2 (1 mL) for 24 hours. The product was purified by
preparative HPLC using a C18 column, 250.times.50 mm, 10.mu., and
eluting with a gradient of 20-100% CHCN vs. 0.1% trifluoroacetic
acid in water, giving the product as a trifluoroacetate salt.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.62 (br
s, 1H), 9.10 (br s, 1H), 8.65 (t, 1H), 8.47 (d, 1H), 7.77 (dd, 1H),
7.70 (br s, 1H), 7.50 (m, 5H), 7.39 (m, 3H), 7.25 (m, 2H), 7.18 (d,
1H), 7.01 (dd, 1H), 6.83 (m, 2H), 6.76 (m, 1H), 6.40 (br s, 1H),
4.70 and 4.15 (both v br s, total 1H), 3.85 (dd, 2H), 3.60 (v br s,
1H), 3.32, 3.27, 3.24, 3.06 (all m, total 11H), 1.90 (m, 1H), 1.62
(m, 3H), 1.30 (m, 4H), 0.70 (br m, 6H).
Example 28
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-(2,4-diox-
o-3-azabicyclo[3.2.0]hept-3-yl)phenyl]sulfonyl}-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 1E for EXAMPLE
27G and
4-(2,4-dioxo-3-azabicyclo[3.2.0]heptan-3-yl)bezenesulfonamide for
EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.87 (br s, 1H), 9.58 (br s,
1H), 7.93 (d, 2H), 7.71 (br s, 1H), 7.54 (m, 7H), 7.35 (m, 5H),
7.10 (dd, 1H), 6.89 (d, 2H), 6.78 (dd, 1H), 6.42 (s, 1H), 4.37 (br
s, 1H), 3.78 (br s, 1H), 3.43 (m, 4H), 3.22, 3.00, 2.85 (all v br
s, total 6H), 2.62 (m, 2H), 2.18 (m, 2H).
Example 29
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-(4-methyl-
-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl]sulfonyl}-2-phenoxybenzamid-
e
This example was prepared by substituting EXAMPLE 1E for EXAMPLE
27G and
4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)bezenesulfonamide
for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.87 (br s, 1H), 11.20 (s, 1H),
9.58 (br s, 1H), 7.90 (d, 2H), 7.83 (d, 2H), 7.50 (m, 5H), 7.32 (m,
5H), 7.08 (dd, 1H), 6.85 (d, 2H), 6.76 (dd, 1H), 6.43 (s, 1H), 4.38
(br s, 1H), 3.80 (br s, 1H), 3.60 (m, 2H), 3.40 (m, 2H), 3.21,
3.00, 2.84 (all br s, total 6H), 2.75 (dd, 1H), 2.28 (d, 1H), 1.08
(d, 3H).
Example 30
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-(3,3-dime-
thyl-2-oxoazetidin-1-yl)phenyl]sulfonyl}-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 1E for EXAMPLE
27G and 4-(3,3-dimethyl-2-oxoazetidin-1-yl)bezenesulfonamide for
EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.62 (br s, 1H), 9.58 (br s,
1H), 7.80 (d, 2H), 7.72 (br s, 1H), 7.50 (m, 5H), 7.40 (m, 4H),
7.33 (m, 3H), 7.08 (dd, 1H), 6.85 (d, 2H), 6.76 (dd, 1H), 6.41 (s,
1H), 4.38 (br s, 1H), 3.77 (br s, 1H), 3.58 (s, 2H), 3.45 (m, 2H),
3.21, 3.00, 2.84 (all br s, total 6H), 1.32 (s, 6H).
Example 31
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-(4-nitro--
2H-1,2,3-triazol-2-yl)phenyl]sulfonyl}-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 1E for EXAMPLE
27G and 4-(4-nitro-2H-1,2,3-triazol-2-yl)bezenesulfonamide for
EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.98 (br s, 1H), 9.58 (br s,
1H), 9.11 (s, 1H), 8.21 (d, 2H), 8.05 (d, 2H), 7.70 (br s, 1H),
7.50 (m, 5H), 7.39 (m, 2H), 7.30 (m, 1H), 7.24 (m, 2H), 7.00 (dd,
1H), 6.82 (d, 2H), 6.78 (dd, 1H), 6.43 (s, 1H), 4.38 (br s, 1H),
3.77 (br s, 1H), 3.45 (m, 2H), 3.21, 3.00, 2.84 (all br s, total
6H).
Example 32
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-phenoxy-N-{[2-
-(2-piperidin-1-ylethoxy)phenyl]sulfonyl}benzamide
This example was prepared by substituting EXAMPLE 1E for EXAMPLE
27G and 2-(2-(piperidin-1-yl)ethoxy)bezenesulfonamide for EXAMPLE
1F in EXAMPLE 27H. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.65 (br s, 1H), 9.77 (br s, 1H), 8.95 (br s, 1H), 7.80
(dd, 1H), 7.70 (br s, 1H), 7.68 (m, 1H), 7.50 (m, 5H), 7.36 (m,
5H), 7.23 (d, 1H), 7.15 (m, 2H), 6.90 (d, 2H), 6.78 (dd, 1H), 6.42
(s, 1H), 4.40 (m, 3H), 3.80 (br s, 1H), 3.40, 3.20 3.00, 2.90 (all
v br m, total 13H), 1.63 (m, 5H), 1.27 (v br s, 1H).
Example 33
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[3-({[(1-eth-
ylpyrrolidin-2-yl)methyl]amino}carbonyl)-4-methoxyphenyl]sulfonyl}-2-pheno-
xybenzamide
This example was prepared by substituting EXAMPLE 1E for EXAMPLE
27G and
N-((1-ethylpyrrolidin-2-yl)methyl)-2-methoxy-5-sulfamoylbenzamide
for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.75 (br s, 1H), 9.70 (br s,
1H), 9.25 (br s, 1H), 8.62 (t, 1H), 8.25 (d, 1H), 7.90 (dd, 1H),
7.70 (br s, 1H), 7.50 (m, 5H), 7.40 (m, 2H), 7.10 (m, 5H), 7.09
(dd, 1H), 6.85 (d, 2H), 6.76 (dd, 1H), 6.40 (s, 1H), 4.39 (br s,
1H), 3.96 (s, 3H), 3.77 (br s, 1H), 3.60 (m, 4H), 3.55-2.80
(envelope, 10H), 2.12 (m, 1H), 2.00 (m, 1H), 1.85 (m, 2H), 1.23 (t,
3H).
Example 34
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1-naphthylox-
y)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)be-
nzamide
Example 34A
methyl
2-bromo-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoat-
e
This example was prepared by substituting methyl
2-bromo-4-fluorobenzoate for EXAMPLE 1C in EXAMPLE 1D.
Example 34B
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(naphthalen--
1-yloxy)benzoate
This example was prepared by substituting EXAMPLE 34A for EXAMPLE
18E and 1-naphthol for phenol in EXAMPLE 18F.
Example 34C
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(naphthalen-1-yloxy-
)benzoic acid
This example was prepared by substituting EXAMPLE 34B for EXAMPLE
1D in EXAMPLE 1E.
Example 34D
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1-naphthylox-
y)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)be-
nzamide
This example was prepared by substituting EXAMPLE 34C for EXAMPLE
27G in EXAMPLE 27H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.82 (br s, 1H), 9.50 (br s,
1H), 8.58 (t, 1H), 8.29 (d, 1H), 8.18 (d, 1H), 7.85 (d, 1H), 7.70
(br s, 1H), 7.50 (m, 8H), 7.38 (m, 4H), 7.20 (dd, 1H), 6.82 (m,
2H), 6.55 (s, 1H), 6.45 (d, 1H), 4.38 (br s, 1H), 3.85 (dd, 2H),
3.78 (br s, 1H), 3.27 (m, 6H), 3.22, 3.02, 2.85 (all br s, total
6H), 1.84 (m, 1H), 1.60 (m, 2H), 1.29 (m, 2H).
Example 35
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(2-naphthylox-
y)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)be-
nzamide
Example 35A
1-(difluoromethylsulfonyl)-2-fluorobenzene
This example was prepared by substituting EXAMPLE 34A for EXAMPLE
18E and 2-naphthol for phenol in EXAMPLE 18F.
Example 35B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(naphthalen-2-yloxy-
)benzoic acid
This example was prepared by substituting EXAMPLE 35A for EXAMPLE
1D in EXAMPLE 1E.
Example 35C
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(2-naphthylox-
y)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)be-
nzamide
This example was prepared by substituting EXAMPLE 35B for EXAMPLE
27G in EXAMPLE 27H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.80 (br s, 1H), 9.55 (br s,
1H), 8.50 (t, 1H), 8.39 (d, 1H), 7.83 (m, 2H), 7.69 (br s, 1H),
7.64 (d, 1H), 7.50 (m, 6H), 7.37 (m, 5H), 7.18 (dd, 1H), 7.00 (d,
1H), 6.81 (dd, 1H), 6.77 (d, 1H), 6.56 (d, 1H), 4.38 (br s, 1H),
3.85 (dd, 2H), 3.78 (br s, 1H), 3.27 (m, 6H), 3.22, 3.02, 2.85 (all
br s, total 6H), 1.84 (m, 1H), 1.60 (m, 2H), 1.29 (m, 2H).
Example 36
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morph-
olin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(2-naphthyloxy)benzamide
This example was prepared by substituting EXAMPLE 35B for EXAMPLE
27G and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.80 (br s, 1H), 9.61 (br
s, 2H), 8.57 (t, 1H), 8.40 (d, 1H), 7.83 (m, 2H), 7.66 (m, 2H),
7.50 (m, 6H), 7.40 (m, 5H), 7.18 (dd, 1H), 7.02 (d, 1H), 6.81 (d,
1H), 6.57 (s, 1H), 4.38 (br s, 1H), 4.00 (m, 2H), 3.80 (br s, 1H),
3.40 (m, 8H), 3.30-2.80 (envelope, 10H), 1.92 (m, 2H).
Example 37
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(2-naphthylox-
y)-N-({(4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulf-
onyl]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 35B for EXAMPLE
27G and EXAMPLE 163A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.82 (br s, 1H), 9.58
(br s, 1H), 8.03 (d, 1H), 7.90 (m, 2H), 7.70 (d, 1H), 7.69 (br s,
1H), 7.65 (dd, 1H), 7.50 (m, 7H), 7.36 (m, 3H), 7.18 (m, 2H), 7.05
(d, 1H), 6.81 (dd, 1H), 6.75 (d, 1H), 6.56 (d, 1H), 4.38 (br s,
1H), 3.83 (dd, 2H), 3.78 (br s, 1H), 3.23 (m, 4H), 3.22, 3.02, 2.85
(all br s, total 6H), 3.15 (m, 2H), 1.80 (m, 1H), 1.55 (m, 2H),
1.22 (m, 2H).
Example 38
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(quinolin-7-yloxy-
)benzamide
Example 38A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(quinolin-7--
yloxy)benzoate
This example was prepared by substituting EXAMPLE 34A for EXAMPLE
18E and quinolin-7-ol for phenol in EXAMPLE 18F.
Example 38B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(quinolin-7-yloxy)b-
enzoic acid
This example was prepared by substituting EXAMPLE 38A for EXAMPLE
1D in EXAMPLE 1E.
Example 38C
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(quinolin-7-yloxy-
)benzamide
This example was prepared by substituting EXAMPLE 38B for EXAMPLE
27G in EXAMPLE 27H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.80 (d, 1H), 8.48 (t, 1H), 8.35
(d, 1H), 8.32 (d, 1H), 7.90 (d, 1H), 7.74 (m, 1H), 7.59 (m, 2H),
7.50 (m, 4H), 7.45 (dd, 1H), 7.38 (d, 2H), 7.30 (m, 2H), 6.95 (d,
1H), 6.86 (dd, 1H), 6.83 (d, 1H), 6.71 (d, 1H), 4.38 (br s, 1H),
3.85 (dd, 2H), 3.78 (br s, 1H), 3.30-2.80 (envelope, 12H), 1.84 (m,
1H), 1.60 (m, 2H), 1.25 (m, 2H).
Example 39
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(quinolin-6-yloxy-
)benzamide
Example 39A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(quinolin-6--
yloxy)benzoate
This example was prepared by substituting EXAMPLE 34A for EXAMPLE
18E and quinolin-6-ol for phenol in EXAMPLE 18F.
Example 39B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(quinolin-6-yloxy)b-
enzoic acid
This example was prepared by substituting EXAMPLE 39A for EXAMPLE
1D in EXAMPLE 1E.
Example 39C
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(quinolin-6-yloxy-
)benzamide
This example was prepared by substituting EXAMPLE 39B for EXAMPLE
27G in EXAMPLE 27H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) 11.90 (br s, 1H), 9.65 (br s, 1H), 8.80
(d, 1H), 8.46 (t, 1H), 8.35 (d, 1H), 7.90 (d, 1H), 7.72 (m, 1H),
7.50 (m, 6H), 7.45 (dd, 1H), 7.37 (m, 4H), 7.02 (d, 1H), 6.83 (dd,
1H), 6.79 (d, 1H), 6.63 (d, 1H), 4.38 (br s, 1H), 3.85 (dd, 2H),
3.78 (br s, 1H), 3.40-2.80 (envelope 12H), 1.87 (m, 1H), 1.62 (m,
2H), 1.26 (m, 2H).
Example 40
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-y-
loxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)benzamide
Example 40A
1-(triisopropylsilyl)-1H-indol-5-ol
5-Benzyloxy-indole (1.0 g) was treated with NaH (135 mg) and
triisopropylsilyl chloride (1.0 g) in tetrahydrofuran for 1 hour,
purified by flash chromatography (98/2 ethyl acetate/hexanes), then
debenzylated in ethanol (35 mL) using Pearlman's catalyst (0.19 g)
and a hydrogen balloon.
Example 40B
methyl
2-(1H-indol-5-yloxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-
-1-yl)benzoate
This example was prepared by substituting EXAMPLE 34A for EXAMPLE
18E and EXAMPLE 40A for phenol in EXAMPLE 18F. In this example, the
crude material from the ether formation was desilylated using
tetrabutyl ammonium fluoride in tetrahydrofuran/water 95/5 prior to
purification.
Example 40C
2-(1H-indol-5-yloxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)b-
enzoic acid
This example was prepared by substituting EXAMPLE 40B for EXAMPLE
1D in EXAMPLE 1E.
Example 40D
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-y-
loxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)benzamide
This example was prepared by substituting EXAMPLE 40C for EXAMPLE
27G in EXAMPLE 27H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.40 (br s, 1H), 11.17 (s, 1H),
9.50 (v br s, 1H), 8.61 (t, 1H), 8.57 (d, 1H), 7.77 (dd, 1H), 7.70
(br s, 1H), 7.50 (m, 5H), 7.36 (m, 5H), 7.10 (s, 1H), 7.08 (d, 1H),
6.83 (dd, 1H), 6.69 (dd, 1H), 6.37 (m, 1H), 6.21 (d, 1H), 4.30 (br
s, 1H), 3.84 (dd, 2H), 3.70 (br s, 1H), 3.30 (m, 6H), 3.20, 2.95,
2.80 (all br s, total 6H), 1.86 (m, 1H), 1.60 (m, 2H), 1.25 (m,
2H).
Example 41
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(isoquinolin--
5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfo-
nyl)benzamide
Example 41A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(isoquinolin-
-5-yloxy)benzoate
This example was prepared by substituting EXAMPLE 34A for EXAMPLE
18E and isoquinolin-5-ol for phenol in EXAMPLE 18F.
Example 41B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(isoquinolin-5-ylox-
y)benzoic acid
This example was prepared by substituting EXAMPLE 41A for EXAMPLE
1D in EXAMPLE 1E.
Example 41C
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(isoquinolin--
5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfo-
nyl)benzamide
This example was prepared by substituting EXAMPLE 41B for EXAMPLE
27G in EXAMPLE 27H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.90 (br s, 1H), 9.55 (v br s,
1H), 9.26 (s, 1H), 8.47 (m, 2H), 8.14 (d, 1H), 7.99 (d, 1H), 7.65
(br s, 1H), 7.60 (d, 1H), 7.45 (m, 6H), 7.29 (m, 4H), 6.80 (m, 2H),
6.60 (m, 2H), 4.38 (br s, 1H), 3.85 (dd, 2H), 3.78 (br s, 1H), 3.24
(m, 6H), 3.22, 3.00, 2.85 (all br s, total 6H), 1.87 (m, 1H), 1.62
(m, 2H), 1.26 (m, 2H).
Example 42
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dime-
thylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(isoquinolin-5-yloxy)ben-
zamide
This example was prepared by substituting EXAMPLE 41B for EXAMPLE
27G and EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.90 (br s, 1H), 9.38
(v br s, 1H), 9.22 (s, 1H), 8.54 (t, 1H), 8.45 (d, 1H), 8.16 (d,
1H), 7.96 (d, 1H), 7.62 (br s, 1H), 7.56 (d, 1H), 7.50 (d, 1H),
7.45 (m, 5H), 7.29 (m, 4H), 6.80 (m, 2H), 6.60 (m, 2H), 4.23 (br s,
1H), 3.78 (br s, 1H), 3.40 (m, 2H), 3.35-2.80 (envelope, 8H), 3.08
(m, 2H), 2.72, 2.70 (both s, total 6H), 1.87 (m, 2H).
Example 43
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dime-
thylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(quinolin-6-yloxy)benzam-
ide
This example was prepared by substituting EXAMPLE 39B for EXAMPLE
27G and EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.96 (br s, 1H), 9.38
(v br s, 1H), 8.77 (dd, 1H), 8.51 (t, 1H), 8.35 (d, 1H), 8.05 (d,
1H), 7.90 (d, 1H), 7.70 (br s, 1H), 7.50 (m, 6H), 7.38 (m, 5H),
6.98 (d, 1H), 6.83 (dd, 1H), 6.79 (d, 1H), 6.63 (d, 1H), 4.38 (br
s, 1H), 3.78 (br s, 1H), 3.42 (m, 2H), 3.35-2.80 (envelope, 8H),
3.15 (m, 2H), 2.81, 2.79 (both s, total 6H), 1.93 (m, 2H).
Example 44
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dime-
thylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzam-
ide
This example was prepared by substituting EXAMPLE 40C for EXAMPLE
27G and EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.40 (br s, 1H),
11.18 (s, 1H), 9.30 (v br s, 1H), 8.66 (t, 1H), 8.60 (d, 1H), 7.85
(dd, 1H), 7.52 (d, 1H), 7.50 (m, 5H), 7.40 (m, 4H), 7.30 (br s,
1H), 7.14 (s, 1H), 7.10 (d, 1H), 6.84 (dd, 1H), 6.67 (dd, 1H), 6.39
(m, 1H), 6.20 (s, 1H), 4.35 (br s, 1H), 3.78 (br s, 1H), 3.40 (m,
2H), 3.35-2.80 (envelope, 8H), 3.10 (m, 2H), 2.78, 2.76 (both s,
total 6H), 1.95 (m, 2H).
Example 45
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-4-y-
loxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)benzamide
Example 45A
1-(triisopropylsilyl)-1H-indol-4-ol
4-Benzyloxy-indole (1.0 g) was treated with NaH (135 mg) and
triisopropylsilyl chloride (1.0 g) in tetrahydrofuran for 1 hour,
purified by flash chromatography (98/2 ethyl acetate/hexanes), then
debenzylated in ethanol (35 mL) using Pearlman's catalyst (0.19 g)
and a hydrogen balloon.
Example 45B
methyl
2-(1H-indol-4-yloxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-
-1-yl)benzoate
This example was prepared by substituting EXAMPLE 34A for EXAMPLE
18E and EXAMPLE 45A for phenol in EXAMPLE 18F. Here the crude
material from the ether formation was desilated using
tetra-n-butylammonium fluoride in tetrahydrofuran/water 95/5 prior
to purification.
Example 45C
2-(1H-indol-4-yloxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)b-
enzoic acid
This example was prepared by substituting EXAMPLE 45B for EXAMPLE
1D in EXAMPLE 1E.
Example 45D
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-4-y-
loxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)benzamide
This example was prepared by substituting EXAMPLE 45C for EXAMPLE
27G in EXAMPLE 27H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.50 (br s, 1H), 11.24 (s, 1H),
9.50 (v br s, 1H), 8.61 (t, 1H), 8.47 (d, 1H), 7.70 (br s, 1H),
7.64 (dd, 1H), 7.50 (m, 5H), 7.30 (m, 4H), 7.15 (d, 2H), 7.04 (d,
2H), 6.92 (dd, 1H), 6.75 (dd, 1H), 6.33 (m, 2H), 6.23 (s, 1H), 4.30
(br s, 1H), 3.84 (dd, 2H), 3.70 (br s, 1H), 3.30 (m, 6H), 3.20,
2.95, 2.80 (all br s, total 6H), 1.86 (m, 1H), 1.60 (m, 2H), 1.25
(m, 2H).
Example 46
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dime-
thylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzam-
ide
This example was prepared by substituting EXAMPLE 45C for EXAMPLE
27G and EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.50 (v br s, 1H),
11.24 (s, 1H), 9.30 (br s, 1H), 8.66 (t, 1H), 8.53 (d, 1H), 7.85
(dd, 1H), 7.55 (d, 1H), 7.50 (m, 5H), 7.39 (m, 2H), 7.30 (m, 2H),
7.148 (d, 1H), 7.10 (d, 1H), 6.96 (dd, 1H), 6.72 (dd, 1H), 6.41 (d,
1H), 6.32 (s, 1H), 6.23 (s, 1H), 4.35 (br s, 1H), 3.78 (br s, 1H),
3.40 (m, 2H), 3.35-2.80 (envelope, 8H), 3.10 (m, 2H), 2.78, 2.76
(both s, total 6H), 1.95 (m, 2H).
Example 47
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dime-
thylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-6-yloxy)benzam-
ide
Example 47A
1-(triisopropylsilyl)-1H-indol-6-ol
6-Benzyloxy-indole (1.0 g) was treated with NaH (135 mg) and
triisopropylsilyl chloride (1.0 g) in tetrahydrofuran for 1 hour,
purified by flash chromatography (98/2 ethyl acetate/hexanes), then
debenzylated in ethanol (35 mL) using Pearlman's catalyst (0.19 g)
and a hydrogen balloon.
Example 47B
methyl
2-(1H-indol-6-yloxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-
-1-yl)benzoate
This example was prepared by substituting EXAMPLE 34A for EXAMPLE
18E and EXAMPLE 47A for phenol in EXAMPLE 18F. In this example, the
crude material from the ether formation was desilated using
tetrabutyl ammonium fluoride in tetrahydrofuran/water 95/5 prior to
purification.
Example 47C
2-(1H-indol-6-yloxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)b-
enzoic acid
This example was prepared by substituting EXAMPLE 47B for EXAMPLE
1D in EXAMPLE 1E.
Example 47D
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dime-
thylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-6-yloxy)benzam-
ide
This example was prepared by substituting EXAMPLE 47C for EXAMPLE
27G and EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.50 (v br s, 1H),
11.00 (s, 1H), 9.38 (br s, 1H), 8.64 (t, 1H), 8.58 (d, 1H), 7.75
(dd, 1H), 7.65 (br s, 1H), 7.55 (d, 1H), 7.50 (m, 5H), 7.39 (m,
2H), 7.30 (m, 2H), 7.00 (d, 1H), 6.90 (s, 1H), 6.70 (m, 2H), 6.42
(m, 1H), 6.30 (s, 1H), 4.35 (br s, 1H), 3.78 (br s, 1H), 3.40 (m,
2H), 3.35-2.80 (envelope, 8H), 3.10 (m, 2H), 2.78, 2.76 (both s,
total 6H), 1.95 (m, 2H).
Example 48
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(isoquinolin--
7-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benz-
amide
Example 48A
This EXAMPLE was prepared by substituting EXAMPLE 34A for EXAMPLE
18E and isoquinolin-7-ol for phenol in EXAMPLE 18F.
Example 48B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(isoquinolin-7-ylox-
y)benzoic acid
This EXAMPLE was prepared by substituting EXAMPLE 48A for EXAMPLE
1D in EXAMPLE 1E.
Example 48C
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(isoquinolin--
7-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benz-
amide
This EXAMPLE was prepared by substituting EXAMPLE 48B for EXAMPLE
27G and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.98 (v br s, 1H), 9.70 (v
br s, 2H), 9.10 (s, 1H), 8.56 (t, 1H), 8.42 (d, 1H), 8.13 (d, 1H),
7.93 (d, 1H), 7.81 (d, 1H), 7.70 (br s, 1H), 7.60 (m, 2H), 7.50 (m,
5H), 7.40 (d, 2H), 7.35 (m, 1H), 7.14 (d, 1H), 6.84 (m, 2H), 6.70
(d, 1H), 4.38 (br s, 1H), 4.00 (m, 2H), 3.80 (br s, 1H), 3.40 (m,
4H), 3.30-2.80 (envelope, 10H), 3.20 (m, 4H), 1.92 (m, 2H).
Example 49
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dime-
thylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(isoquinolin-7-yloxy)ben-
zamide
This example was prepared by substituting EXAMPLE 48B for EXAMPLE
27G and EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.98 (v br s, 1H),
9.40 (br s, 2H), 9.10 (s, 1H), 8.56 (t, 1H), 8.40 (d, 1H), 8.13 (d,
1H), 7.93 (d, 1H), 7.81 (d, 1H), 7.70 (br s, 1H), 7.60 (m, 2H),
7.50 (m, 5H), 7.40 (d, 2H), 7.35 (m, 1H), 7.14 (d, 1H), 6.84 (m,
2H), 6.70 (d, 1H), 4.38 (br s, 1H), 3.78 (br s, 1H), 3.42 (m, 2H),
3.35-2.80 (envelope, 8H), 3.15 (m, 2H), 2.81, 2.79 (both s, total
6H), 1.93 (m, 2H).
Example 50
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitroph-
enyl}sulfonyl)benzamide
Example 50A
methyl
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-
-1-enyl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 19D for EXAMPLE
34A in EXAMPLE 40B.
Example 50B
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl-
)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 50A for EXAMPLE
1D in EXAMPLE 1E.
Example 50C
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitroph-
enyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 50B for EXAMPLE
27G and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.98 (br s, 1H), 11.20 (s,
1H), 9.70 (v br s, 1H), 9.35 (v br s, 1H), 8.71 (t, 1H), 8.62 (d,
1H), 7.86 (dd, 1H), 7.54 (d, 1H), 7.40 (m, 4H), 7.12 (m, 4H), 6.87
(dd, 1H), 6.70 (dd, 1H), 6.40 (m, 1H), 6.20 (d, 1H), 3.98 (m, 2H),
3.50, 3.40, 3.30 (all m, total 12H), 3.19 (m, 2H), 3.00 (m, 4H),
2.75 (br s, 2H), 2.23 (br m, 2H), 1.97 (br m, 2H), 1.43 (br t, 2H),
0.98 (s, 6H).
Example 51
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 50B for EXAMPLE
27G and EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.42 (br s, 1H),
11.20 (s, 1H), 9.40 (v br s, 1H), 9.30 (v br s, 1H), 8.66 (t, 1H),
8.61 (d, 1H), 7.86 (dd, 1H), 7.54 (d, 1H), 7.40 (m, 4H), 7.18 (d,
1H), 7.12 (m, 3H), 6.87 (dd, 1H), 6.70 (dd, 1H), 6.40 (s, 1H), 6.20
(s, 1H), 3.60 (br s, 2H), 3.50 (m, 4H), 3.35 (br s, 2H), 3.13 (m,
3H), 3.00 (br m, 2H), 2.78, 2.77 (both s, total 6H), 2.70 (br s,
1H), 2.12 (br m, 2H), 1.97 (m, 4H), 1.42 (br t, 2H), 0.97 (s,
6H).
Example 52
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitroph-
enyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
27G and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.40 (br s, 1H), 11.20 (s,
1H), 9.60 (v br s, 1H), 9.25 (v br s, 1H), 8.70 (t, 1H), 8.62 (d,
1H), 7.86 (dd, 1H), 7.54 (d, 1H), 7.40 (m, 4H), 7.18 (d, 1H), 7.13
(d, 1H), 7.09 (d, 2H), 6.87 (dd, 1H), 6.70 (dd, 1H), 6.40 (m, 1H),
6.20 (s, 1H), 3.98 (m, 2H), 3.50, 3.40, 3.30 (all m, total 12H),
3.19 (m, 2H), 3.00 (m, 4H), 2.75 (br s, 2H), 2.18 (br m, 2H), 2.00
(br m, 4H), 1.43 (br t, 2H), 0.96 (s, 6H).
Example 53
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(H--
indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
27G and EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.41 (br s, 1H),
11.20 (s, 1H), 9.35 (v br s, 2H), 8.66 (t, 1H), 8.62 (d, 1H), 7.86
(dd, 1H), 7.54 (d, 1H), 7.40 (m, 4H), 7.18 (d, 1H), 7.13 (d, 1H),
7.09 (d, 2H), 6.87 (dd, 1H), 6.70 (dd, 1H), 6.40 (m, 1H), 6.20 (s,
1H), 3.50 (m, 4H), 3.35 (br s, 2H), 3.13 (m, 3H), 3.00 (br m, 2H),
2.78, 2.77 (both s, total 6H), 2.70 (br s, 1H), 2.20 (br m, 2H),
2.00 (m, 2H), 1.93 (m, 2H), 1.42 (br t, 2H), 0.97 (s, 6H).
Example 54
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitroph-
enyl}sulfonyl)benzamide
Example 54A
methyl
2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-
-1-enyl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 19D for EXAMPLE
34A in EXAMPLE 45B.
Example 54B
2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl-
)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 54A for EXAMPLE
1D in EXAMPLE 1E.
Example 54C
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitroph-
enyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 54B for EXAMPLE
27G and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.50 (br s, 1H), 11.27 (s,
1H), 9.60 (v br s, 1H), 9.20 (v br s, 1H), 8.65 (t, 1H), 8.55 (d,
1H), 7.80 (dd, 1H), 7.57 (d, 1H), 7.40 (d, 2H), 7.30 (dd, 1H), 7.12
(d, 2H), 7.10 (d, 2H), 7.00 (dd, 1H), 6.73 (dd, 1H), 6.46 (d, 1H),
6.30 (s, 1H), 6.23 (m, 1H), 3.98 (m, 2H), 3.60, 3.50, 3.40 (all m,
total 12H), 3.19 (m, 2H), 3.00 (m, 4H), 2.75 (br s, 2H), 2.23 (br
m, 2H), 1.97 (br m, 4H), 1.43 (br t, 2H), 0.98 (s, 6H).
Example 55
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitroph-
enyl}sulfonyl)benzamide
Example 55A
methyl
2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-enyl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 45A for phenol in
EXAMPLE 18F. Here the crude material from the ether formation was
desilated using tetrabutyl ammonium fluoride in
tetrahydrofuran/water 95/5 prior to purification.
Example 55B
2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl-
)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 55A for EXAMPLE
1D in EXAMPLE 1E.
Example 55C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitroph-
enyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
27G and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.50 (br s, 1H), 11.25 (s,
1H), 9.60 (v br s, 1H), 9.20 (v br s, 1H), 8.65 (t, 1H), 8.55 (d,
1H), 7.80 (dd, 1H), 7.57 (d, 1H), 7.40 (d, 2H), 7.30 (dd, 1H), 7.20
(d, 1H), 7.10 (m, 3H), 7.00 (dd, 1H), 6.73 (dd, 1H), 6.46 (d, 1H),
6.30 (s, 1H), 6.23 (m, 1H), 3.98 (m, 2H), 3.60, 3.50, 3.40 (all m,
total 12H), 3.19 (m, 2H), 3.00 (m, 4H), 2.75 (br s, 2H), 2.20 (br
m, 2H), 2.00 (br m, 4H), 1.43 (br t, 2H), 0.98 (s, 6H).
Example 56
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 54B for EXAMPLE
27G and EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.55 (br s, 1H),
11.27 (s, 1H), 9.40 (v br s, 1H), 9.35 (v br s, 1H), 8.65 (t, 1H),
8.55 (d, 1H), 7.79 (dd, 1H), 7.57 (d, 1H), 7.40 (d, 2H), 7.30 (dd,
1H), 7.20 (d, 1H), 7.10 (m, 3H), 7.00 (dd, 1H), 6.73 (dd, 1H), 6.46
(d, 1H), 6.30 (s, 1H), 6.23 (m, 1H), 3.50 (m, 4H), 3.35 (br s, 2H),
3.13 (m, 3H), 3.00 (br m, 2H), 2.78, 2.77 (both s, total 6H), 2.70
(br s, 1H), 2.22 (br m, 2H), 1.97 (m, 2H), 1.93 (m, 2H), 1.42 (br
t, 2H), 0.97 (s, 6H).
Example 57
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
27G and EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.50 (br s, 1H),
11.25 (s, 1H), 9.60 (v br s, 1H), 9.20 (v br s, 1H), 8.65 (t, 1H),
8.55 (d, 1H), 7.79 (dd, 1H), 7.57 (d, 1H), 7.40 (d, 2H), 7.30 (dd,
1H), 7.20 (d, 1H), 7.10 (m, 3H), 7.00 (dd, 1H), 6.73 (dd, 1H), 6.46
(d, 1H), 6.30 (s, 1H), 6.23 (m, 1H), 3.50 (m, 4H), 3.35 (br s, 2H),
3.13 (m, 3H), 3.00 (br m, 2H), 2.78, 2.77 (both s, total 6H), 2.70
(br s, 1H), 2.20 (br m, 2H), 2.00 (m, 2H), 1.93 (m, 2H), 1.42 (br
t, 2H), 0.97 (s, 6H).
Example 58
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-4-y-
loxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzami-
de
This example was prepared by substituting EXAMPLE 45C for EXAMPLE
27G and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.50 (br s, 1H), 11.24 (s,
1H), 9.50 (v br s, 1H), 8.67 (t, 1H), 8.52 (d, 1H), 7.78 (dd, 1H),
7.70 (br s, 1H), 7.55 (d, 1H), 7.50 (m, 4H), 7.38 (d, 2H), 7.30
(dd, 2H), 7.18 (d, 1H), 7.08 (d, 1H), 6.96 (dd, 1H), 6.75 (dd, 1H),
6.40 (d, 1H), 6.33 (s, 1H), 6.23 (s, 1H), 4.38 (br s, 1H), 4.00 (m,
2H), 3.80 (br s, 1H), 3.40 (m, 4H), 3.30-2.80 (envelope, 10H), 3.20
(m, 4H), 1.95 (m, 2H).
Example 59
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-y-
loxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzami-
de
This example was prepared by substituting EXAMPLE 40C for EXAMPLE
27G and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.40 (br s, 1H), 11.19 (s,
1H), 9.60 (v br s, 1H), 8.69 (t, 1H), 8.60 (d, 1H), 7.83 (dd, 1H),
7.65 (br s, 1H), 7.50 (m, 5H), 7.38 (m, 5H), 7.12 (m, 2H), 6.83
(dd, 1H), 6.69 (dd, 1H), 6.39 (m, 1H), 6.20 (d, 1H), 4.38 (br s,
1H), 4.00 (m, 2H), 3.80 (br s, 1H), 3.40 (m, 4H), 3.30-2.80
(envelope, 10H), 3.20 (m, 4H), 1.96 (m, 2H).
Example 60
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-methoxyph-
enyl)sulfonyl]-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 1E for EXAMPLE
27G and 4-methoxybenzenesulfonamide for EXAMPLE 1F in EXAMPLE 27H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.57 (s,
1H), 7.74 (d, 2H), 7.50 (m, 5H), 7.35 (m, 6H), 7.10 (t, 1H), 7.02
(m, 2H), 6.87 (d, 2H), 6.75 (dd, 1H), 6.41 (s, 1H), 4.36 (m, 2H),
3.83 (s, 3H), 3.76 (m, 2H), 3.23 (m, 2H), 3.01 (m, 2H), 2.84 (m,
2H).
Example 61
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-methylphe-
nyl)sulfonyl]-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 1E for EXAMPLE
27G and 4-methylbenzenesulfonamide for EXAMPLE 1F in EXAMPLE 27H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.64 (s,
1H), 7.68 (d, 2H), 7.50 (m, 5H), 7.38 (m, 2H), 7.32 (m, 6H), 7.11
(t, 1H), 6.87 (d, 2H), 6.75 (dd, 1H), 6.41 (s, 1H), 4.36 (m, 2H),
3.76 (m, 2H), 3.23 (m, 2H), 3.01 (m, 2H), 2.84 (m, 2H), 2.37 (s,
3H).
Example 62
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-y-
loxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)su-
lfonyl]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 40C for EXAMPLE
27G and EXAMPLE 163A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.46 (s, 1H), 11.16
(s, 1H), 8.17 (d, 1H), 7.88 (dd, 1H), 7.68 (br s, 1H), 7.50 (m,
5H), 7.36 (m, 6H), 7.13 (s, 1H), 7.03 (d, 1H), 6.84 (dd, 1H), 6.68
(dd, 1H), 6.39 (m, 1H), 6.21 (br s, 1H), 4.32 (s, 2H), 3.84 (dd,
2H), 3.25 (m, 7H), 2.93 (m, 4H), 1.84 (m, 2H), 1.54 (m, 2H), 1.24
(m, 2H).
Example 63
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-4-y-
loxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)su-
lfonyl]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 45C for EXAMPLE
27G and EXAMPLE 163A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.58 (s, 1H), 11.27
(s, 1H), 8.12 (d, 1H), 7.71 (m, 2H), 7.52 (m, 5H), 7.32 (m, 5H),
7.18 (d, 1H), 6.96 (m, 2H), 6.74 (dd, 1H), 6.36 (m, 2H), 6.26 (m,
1H), 4.32 (s, 2H), 3.84 (dd, 2H), 3.25 (m, 7H), 2.93 (m, 4H), 1.84
(m, 2H), 1.54 (m, 2H), 1.24 (m, 2H).
Example 64
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-{[3-(dime-
thylamino)propyl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1-
H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 40C and EXAMPLE
170A for EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.46 (br
s, 1H), 11.18 (s, 1H), 8.21 (d, 1H), 7.98 (dd, 1H), 7.50 (m, 6H),
7.41 (m, 5H), 7.29 (br s, 1H), 7.17 (s, 1H), 7.08 (d, 1H), 6.84
(dd, 1H), 6.68 (dd, 1H), 6.40 (m, 1H), 6.18 (br s, 1H), 4.32 (br s,
2H), 3.59 (m, 4H), 3.25 (m, 2H), 3.05 (m, 4H), 2.90 (m, 2H), 2.77
(d, 6H), 1.88 (m, 2H).
Example 65
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-4-y-
loxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]p-
henyl}sulfonyl)benzamide
Example 65A
4-(3-morpholinopropylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide
This example was prepared by substituting EXAMPLE 159C and
3-morpholinopropan-1-amine for 4-fluoro-3-nitrobenzenesulfonamide
and (tetrahydropyran-4-yl)methylamine respectively, in EXAMPLE
1F.
Example 65B
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-4-y-
loxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]p-
henyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 40C and EXAMPLE
65A for EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.46 (br
s, 1H), 11.18 (s, 1H), 8.18 (d, 1H), 7.91 (m, 1H), 7.50 (m, 6H),
7.41 (m, 5H), 7.30 (m, 1H), 7.19 (d, 1H), 7.08 (m, 1H), 6.99 (m,
1H), 6.72 (dd, 1H), 6.48 (br s, 1H), 6.25 (m, 1H), 4.29 (br s, 2H),
4.01 (m; 2H) 3.59 (m, 2H), 3.41 (m, 4H), 3.05 (m, 10H), 2.58 (m,
2H), 1.91 (m, 2H).
Example 66
N-[(3-{[chloro(difluoro)methyl]sulfonyl}-4-{[3-(dimethylamino)propyl]amino-
}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl-
]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide
Example 66A
(difluoromethyl)(2-fluorophenyl)sulfane
Powdered NaOH (31.2 g), tris(2-(2-methoxyethoxy)ethyl)amine (5 mL)
and 2-fluorobenzene thiol (33.6 mL) in benzene (400 mL) was
saturated with chlorodifluoromethane, stirred at 80.degree. C. for
30 minutes and filtered through diatomaceous earth (Celite.RTM.).
The filtrate was washed with saturated NaHCO.sub.3 and the water
layer was extracted with diethyl ether. The extracts were combined
and dried (MgSO.sub.4), filtered and concentrated.
Example 66B
1-(difluoromethylsulfonyl)-2-fluorobenzene
EXAMPLE 66A (46 g) in 1:1:2 CCl.sub.4/CH.sub.3CN/water (1.2 L) at
25.degree. C. was treated with NaIO.sub.4 (164.6 g) and
RuCl.sub.3.xH.sub.2O (534 mg), stirred for 18 hours, diluted with
dichloromethane and filtered through diatomaceous earth
(Celite.RTM.). The filtrate was washed with saturated NaHCO.sub.3
and dried (Na.sub.2SO.sub.4), filtered and concentrated. The
concentrate was filtered through silica gel.
Example 66C
1-(chlorodifluoromethylsulfonyl)-2-fluorobenzene
EXAMPLE 66B (25 g) and N-chlorosuccinimide (17.55 g) in
tetrahydrofuran (690 mL) at -78.degree. C. was treated with lithium
hexamethyldisilazide (178.5 mL) over 1 hour, stirred for 1 hour and
quenched with ammonium chloride. The mixture was extracted with
ethyl acetate, and the extract was washed with brine and dried
(MgSO.sub.4), filtered and concentrated. The concentrate was
chromatographed on silica gel with 0-5% ethyl acetate/hexanes.
Example 66D
3-(chlorodifluoromethylsulfonyl)-4-fluorobenzene-1-sulfonyl
chloride
EXAMPLE 66C (44 g) in chlorosulfonic acid (36.7 mL) at 120.degree.
C. was stirred for 18 hours, cooled to 25.degree. C., pipetted onto
crushed ice and extracted with ethyl acetate. The extract was
washed with water and brine and dried (MgSO.sub.4), filtered and
concentrated.
Example 66E
3-(chlorodifluoromethylsulfonyl)-4-fluorobenzenesulfonamide
EXAMPLE 66D (22 g) in isopropanol (690 mL) at -78.degree. C. was
treated with aqueous ammonia (90 mL) over 1 hour, stirred for
another hour, quenched with 6M HCl (300 mL), warmed to 25.degree.
C. and concentrated. The concentrate was mixed with water and
extracted with ethyl acetate. The extract was dried (MgSO.sub.4),
filtered and concentrated. The concentrate was recrystallized from
hexanes/ethyl acetate.
Example 66F
3-(chlorodifluoromethylsulfonyl)-4-(3-(dimethylamino)propylamino)benzenesu-
lfonamide
This example was prepared by substituting EXAMPLE 66E and
N,N-dimethylpropane-1,3-diamine for
4-fluoro-3-nitrobenzenesulfonamide and
(tetrahydropyran-4-yl)methylamine respectively, in EXAMPLE 1F.
Example 66G
N-[(3-{[chloro(difluoro)methyl]sulfonyl}-4-{[3-(dimethylamino)propyl]amino-
}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl-
]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 54B and EXAMPLE
66F for EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.20 (s,
1H), 8.28 (m, 1H), 7.99 (m, 1H), 7.55 (m, 2H), 7.38 (m, 2H), 7.21
(m, 3H), 7.09 (d, 2H), 6.98 (m, 1H), 6.71 (m, 1H), 6.41 (m, 2H),
6.21 (m, 1H), 3.57 (m, 2H), 3.28 (m, 4H), 2.84 (m, 6H), 2.67 (m,
5H), 2.19 (m, 2H), 2.02 (m, 2H), 1.77 (br s, 2H), 1.61 (m, 2H),
1.46 (m, 2H), 0.94 (s, 6H).
Example 67
N-[(3-{[chloro(difluoro)methyl]sulfonyl}-4-{[3-(dimethylamino)propyl]amino-
}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl-
]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 26C and EXAMPLE
66F for EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.20 (s,
1H), 8.28 (m, 1H), 8.05 (m, 1H), 7.99 (m, 1H), 7.55 (m, 2H), 7.38
(m, 2H), 7.21 (m, 3H), 7.09 (d, 2H), 6.98 (m, 1H), 6.71 (m, 1H),
6.41 (m, 2H), 6.21 (m, 1H), 3.57 (m, 2H), 3.28 (m, 4H), 3.05 (m,
2H), 2.96 (m, 2H), 2.88 (s, 3H), 2.78 (m, 2H), 2.68 (m, 3H), 2.19
(m, 2H), 2.01 (br s, 2H), 1.72 (m, 2H), 1.45 (m, 2H), 0.93 (s,
6H).
Example 68
2-(1H-indol-4-yloxy)-4-(4-{[2-(4-methoxyphenyl)-4,4-dimethylcyclohex-1-en--
1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]-
phenyl}sulfonyl)benzamide
Example 68A
(2-bromo-4,4-dimethylcyclohex-1-enyl)methanol
N,N-dimethylformamide (18.41 ml) was taken up in chloroform (64 ml)
and the resulting solution was cooled in an ice bath. Phosphorus
tribromide (20.18 ml) was added dropwise over 15 minutes. The
resulting suspension was then heated to 70.degree. C. for 30
minutes. A solution of 3,3-dimethylcyclohexanone (10 g) in
chloroform (21 ml) was added dropwise over 30 minutes. The mixture
was stirred at 70.degree. C. for another 2 hours. The mixture was
then allowed to cool to room temperature. The solution was
cautiously poured over ice. Solid sodium bicarbonate was added to
neutralize acid. The mixture was extracted three times with ether,
and the extracts were washed with water and brine and dried
(MgSO.sub.4). The solvent was removed under vacuum, and the crude
material was flushed through a silica plug with ether as the
eluent. After concentration, the crude material was dissolved in
methanol. Sodium borohydride (1.757 g) was added cautiously. The
resulting mixture was stirred at room temperature overnight, and
diluted with ethyl acetate. The mixture was washed with water and
brine and dried (MgSO.sub.4). The solvent was removed under vacuum,
and the residue was purified by flash chromatography eluting with
20% ethyl acetate in hexanes to 100% ethyl acetate.
Example 68B
methyl 2-(1H-indol-4-yloxy)-4-(piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 24F and
piperazine for EXAMPLE 1C and EXAMPLE 1B respectively, in EXAMPLE
1D.
Example 68C
methyl
2-(1H-indol-4-yloxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-enyl)met-
hyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 68A and EXAMPLE
68B for EXAMPLE 18C and EXAMPLE 18D respectively, in EXAMPLE
18E.
Example 68D
methyl
2-(1H-indol-4-yloxy)-4-(4-((2-(4-methoxyphenyl)-4,4-dimethylcyclohe-
x 1-enyl)methyl)piperazin-1-yl)benzoate
EXAMPLE 68C (142 mg), 4-methoxyphenylboronic acid (45.6 mg),
bis(triphenylphosphine)palladium(II) dichloride (8.7 mg), and
cesium fluoride (114 mg) were combined in dimethoxyethane (0.9 mL)
and methanol (0.4 mL) and heated to 90.degree. C. for 2 hours. The
reaction mixture was diluted with ethyl acetate and poured into
water. The organic layer was washed with water and with brine,
dried (MgSO.sub.4), filtered, and concentrated. The resulting solid
was triturated with methanol, and filtered.
Example 68E
2-(1H-indol-4-yloxy)-4-(4-((2-(4-methoxyphenyl)-4,4-dimethylcyclohex-1-eny-
l)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 68D for EXAMPLE
1D in EXAMPLE 1E.
Example 68F
3-nitro-4-(3-(pyrrolidin-1-yl)propylamino)benzenesulfonamide
This example was prepared by substituting
3-(pyrrolidin-1-yl)propan-1-amine for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 68G
2-(1H-indol-4-yloxy)-4-(4-{[2-(4-methoxyphenyl)-4,4-dimethylcyclohex-1-en--
1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]-
phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 68E and EXAMPLE
68F for EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.56
(brs, 1H), 11.26 (s, 1H), 8.66 (t, 1H), 8.53 (d, 1H), 7.78 (dd,
1H), 7.56 (d, 1H), 7.29 (t, 1H), 7.19 (d, 1H), 7.10 (d, 1H), 6.98
(m, 3H), 6.88 (m, 2H), 6.74 (m, 1H), 6.43 (d, 1H), 6.36 (br s, 1H),
6.23 (m, 1H), 3.73 (s, 3H), 3.62 (m, 2H), 3.52 (m, 4H), 3.22 (m,
4H), 2.99 (m, 4H), 2.18 (m, 2H), 1.99 (m, 6H), 1.84 (m, 2H), 1.45
(m, 2H), 1.23 (m, 2H), 0.94 (s, 6H).
Example 69
4-[4-({4,4-dimethyl-2-[4-(trifluoromethyl)phenyl]cyclohex-1-en-1-yl}methyl-
)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpro-
pyl)amino]phenyl}sulfonyl)benzamide
Example 69A
methyl
2-(1H-indol-4-yloxy)-4-(4-((4,4-dimethyl-2-(4-(trifluoromethyl)phen-
yl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting
4-(trifluoromethyl)phenylboronic acid for 4-methoxyphenylboronic
acid in EXAMPLE 68D.
Example 69B
2-(1H-indol-4-yloxy)-4-(4-((4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)cycl-
ohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 69A for EXAMPLE
1D in EXAMPLE 1E.
Example 69C
4-[4-({4,4-dimethyl-2-[4-(trifluoromethyl)phenyl]cyclohex-1-en-1-yl}methyl-
)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpro-
pyl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 69B and EXAMPLE
68F for EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.55 (br
s, 1H), 11.26 (s, 1H). 8.66 (t. 1H), 8.53 (d_1H) 778 (m, 1H), 7.67
(m, 2H), 7.56 (m, 1H), 7.29 (m, 3H), 7.19 (d, 1H), 7.10 (d, 1H),
6.98 (m, 1H), 6.72 (m, 1H), 6.46 (m, 1H), 6.36 (br s, 1H), 6.23 (m,
1H), 3.62 (m, 4H), 3.52 (m, 4H), 3.18 (m, 4H), 3.02 (m, 4H), 2.19
(m, 2H), 2.02 (m, 6H), 1.82 (m, 2H), 1.47 (m, 2H), 0.94 (s,
6H).
Example 70
4-[4-({4,4-dimethyl-2-[4-(trifluoromethoxy)phenyl]cyclohex-1-en-1-yl}methy-
l)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpr-
opyl)amino]phenyl}sulfonyl)benzamide
Example 70A
methyl
2-(1H-indol-4-yloxy)-4-(4-((4,4-dimethyl-2-(4-(trifluoromethoxy)phe-
nyl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting
4-(trifluoromethoxy)phenylboronic acid for 4-methoxyphenylboronic
acid in EXAMPLE 68D.
Example 70B
2-(1H-indol-4-yloxy)-4-(4-((4,4-dimethyl-2-(4-(trifluoromethoxy)phenyl)cyc-
lohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 70A for EXAMPLE
1D in EXAMPLE 1E.
Example 70C
4-[4-({4,4-dimethyl-2-[4-(trifluoromethoxy)phenyl]cyclohex-1-en-1-yl}methy-
l)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpr-
opyl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 70B and EXAMPLE
68F for EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.56 (br
s, 1H), 11.26 (s, 1H), 8.66 (t, 1H), 8.54 (d, 1H), 7.80 (m, 1H),
7.63 (m, 2H), 7.56 (m, 3H), 7.29 (m, 2H), 7.19 (m, 2H), 6.98 (m,
1H), 6.72 (m, 1H), 6.46 (m, 1H), 6.23 (m, 1H), 3.62 (m, 4H), 3.52
(m, 4H), 3.18 (m, 4H), 3.02 (m, 4H), 2.19 (m, 2H), 2.02 (m, 6H),
1.82 (m, 2H), 1.47 (m, 2H), 0.94 (s, 6H).
Example 71
4-[4-({4,4-dimethyl-2-[3-(trifluoromethyl)phenyl]cyclohex-1-en-1-yl}methyl-
)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpro-
pyl)amino]phenyl}sulfonyl)benzamide
Example 71A
methyl
2-(1H-indol-4-yloxy)-4-(4-((4,4-dimethyl-2-(3-(trifluoromethyl)phen-
yl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting
3-(trifluoromethyl)phenylboronic acid for 4-methoxyphenylboronic
acid in EXAMPLE 68D.
Example 71B
2-(1H-indol-4-yloxy)-4-(4-((4,4-dimethyl-2-(3-(trifluoromethyl)phenyl)cycl-
ohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 71A for EXAMPLE
1D in EXAMPLE 1E.
Example 71C
4-[4-({4,4-dimethyl-2-[3-(trifluoromethyl)phenyl]cyclohex-1-en-1-yl}methyl-
)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpro-
pyl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 71B and EXAMPLE
68F for EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.55 (br
s, 1H), 11.26 (s, 1H), 8.65 (t, 1H), 8.54 (d, 1H), 7.80 (dd, 1H),
7.63 (m, 2H), 7.56 (m, 3H), 7.38 (m, 2H), 7.29 (t, 1H), 7.19 (d,
1H), 7.11 (d, 1H), 6.98 (t, 1H), 6.72 (m, 1H), 6.46 (m, 1H), 6.31
(m, 1H), 6.23 (m, 1H), 3.58 (m, 7H), 3.18 (m, 4H), 3.02 (m, 4H),
2.19 (m, 3H), 2.02 (m, 6H), 1.82 (m, 2H), 1.47 (m, 2H), 0.96 (s,
6H).
Example 72
4-(4-{[2-(3-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]p-
henyl}sulfonyl)benzamide
Example 72A
methyl
2-(1H-indol-4-yloxy)-4-(4-((2-(3-fluorophenyl)-4,4-dimethylcyclohex-
-1-enyl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting 3-fluorophenylboronic
acid for 4-methoxyphenylboronic acid in EXAMPLE 68D.
Example 72B
2-(1H-indol-4-yloxy)-4-(4-((2-(3-fluorophenyl)-4,4-dimethylcyclohex-1-enyl-
)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 72A for EXAMPLE
1D in EXAMPLE 1E.
Example 72C
4-(4-{[2-(3-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]p-
henyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 72B and EXAMPLE
68F for EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.55 (br
s, 1H), 11.26 (s, 1H), 8.65 (t, 1H), 8.54 (d, 1H), 7.80 (m, 1H),
7.63 (m, 2H), 7.56 (m, 3H), 7.38 (m, 2H), 7.29 (t, 1H), 7.19 (d,
1H), 7.11 (d, 1H), 6.98 (m, 1H), 6.72 (m, 1H), 6.46 (m, 1H), 6.31
(m, 1H), 6.23 (m, 1H), 3.58 (m, 7H), 3.18 (m, 4H), 3.02 (m, 4H),
2.19 (m, 3H), 2.02 (m, 6H), 1.82 (m, 2H), 1.47 (m, 2H), 0.96 (s,
6H).
Example 73
4-(4-{[2-(4-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]p-
henyl}sulfonyl)benzamide
Example 73A
methyl
2-(1H-indol-4-yloxy)-4-(4-((2-(4-fluorophenyl)-4,4-dimethylcyclohex-
-1-enyl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting 4-fluorophenylboronic
acid for 4-methoxyphenylboronic acid in EXAMPLE 68D.
Example 73B
2-(1H-indol-4-yloxy)-4-(4-((2-(4-fluorophenyl)-4,4-dimethylcyclohex-1-enyl-
)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 73A for EXAMPLE
1D in EXAMPLE 1E.
Example 73C
4-(4-{[2-(4-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]p-
henyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 73B and EXAMPLE
68F for EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.56 (br
s, 1H), 11.26 (s, 1H), 8.66 (t, 1H), 8.54 (d, 1H), 7.80 (m, 1H),
7.63 (m, 2H), 7.56 (m, 3H), 7.29 (m, 2H), 7.19 (m, 2H), 6.98 (m,
1H), 6.72 (m, 1H), 6.46 (m, 1H), 6.23 (m, 1H), 3.62 (m, 4H), 3.52
(m, 4H), 3.18 (m, 4H), 3.02 (m, 4H), 2.19 (m, 2H), 2.02 (m, 6H),
1.82 (m, 2H), 1.47 (m, 2H), 0.94 (s, 6H).
Example 74
N-({3-{[chloro(difluoro)methyl]sulfonyl}-4-[(1-methylpiperidin-4-yl)amino]-
phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]-
methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide
Example 74A
3-(chlorodifluoromethylsulfonyl)-4-(1-methylpiperidin-4-ylamino)benzenesul-
fonamide
This example was prepared by substituting EXAMPLE 66E and
1-methylpiperidin-4-amine for 4-fluoro-3-nitrobenzenesulfonamide
and (tetrahydropyran-4-yl)methylamine respectively, in EXAMPLE
1F.
Example 74B
N-({3-{[chloro(difluoro)methyl]sulfonyl}-4-[(1-methylpiperidin-4-yl)amino]-
phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]-
methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 26C and EXAMPLE
74A for EXAMPLE 1E and EXAMPLE 1F respectively, in EXAMPLE 1G.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.07 (s,
1H), 8.11 (d, 1H), 7.89 (dd, 1H), 7.50 (d, 1H), 7.34 (m, 4H), 7.05
(m, 3H), 6.96 (d, 1H), 6.78 (dd, 1H), 6.60 (m, 2H), 6.36 (s, 1H),
6.13 (d, 1H), 3.67 (m, 1H), 2.97 (m, 6H), 2.71 (s, 2H), 2.59 (m,
2H), 2.46 (s, 3H), 2.16 (m, 6H), 1.98 (m, 4H), 1.55 (m, 2H), 1.38
(t, 2H), 0.92 (s, 6H).
Example 75
4-(4-{[2-(4-chlorophenyl)cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-i-
ndol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl-
)benzamide
Example 75A
methyl
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)cyclohex-1-enyl)methy-
l)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 149D and EXAMPLE
150A for 4'-chlorobiphenyl-2-carboxaldehyde and
tert-butylpiperazine-1-carboxylate respectively, in EXAMPLE 1A.
Example 75B
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)cyclohex-1-enyl)methyl)piper-
azin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 75A for EXAMPLE
1D in EXAMPLE 1E.
Example 75C
4-(4-{[2-(4-chlorophenyl)cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-i-
ndol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl-
)benzamide
This example was prepared by substituting EXAMPLE 75B and EXAMPLE
21A for EXAMPLE 1E and EXAMPLE 1F respectively, in EXAMPLE 1G.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.07 (s,
1H), 8.52 (d, 1H), 8.12 (d, 1H), 7.79 (dd, 1H), 7.52 (d, 1H), 7.34
(m, 4H), 7.05 (m, 4H), 6.79 (dd, 1H), 6.59 (dd, 1H), 6.36 (s, 1H),
6.13 (d, 1H), 3.72 (m, 1H), 2.97 (m., 6H), 2.69 (s, 2H) 2.59 (m,
2H), 2.46 (s 3H), 2.16 (m, 6H), 2.11 (m, 2H), 1.98 (m, 2H), 1.70
(m, 2H), 1.62 (m, 4H).
Example 76
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifl-
uoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
Example 76A
4-(1-methylpiperidin-4-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonam-
ide
This example was prepared by substituting EXAMPLE 159C and
1-methylpiperidin-4-amine for 4-fluoro-3-nitrobenzenesulfonamide
and (tetrahydropyran-4-yl)methylamine respectively, in EXAMPLE
1F.
Example 76B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifl-
uoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 26C and EXAMPLE
76A for EXAMPLE 1E and EXAMPLE 1F respectively, in EXAMPLE 1G.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.08 (s,
1H), 8.11 (d, 1H), 7.89 (dd, 1H), 7.50 (d, 1H), 7.34 (m, 4H), 7.05
(m, 3H), 6.98 (d, 1H), 6.78 (dd, 1H), 6.60 (m, 2H), 6.36 (t, 1H),
6.13 (d, 1H), 3.67 (br s, 1H), 2.97 (m, 6H), 2.71 (s, 3H), 2.63 (m,
1H), 2.47 (s, 3H), 2.17 (m, 6H), 1.98 (m, 4H), 1.60 (m, 2H), 1.38
(t, 2H), 0.92 (s, 6H).
Example 77
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(phenoxymethyl)be-
nzamide
Example 77A
5-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)isobenzofuran-1(3H)-on-
e
5-bromoisobenzofuran-1(3H)-one (400 mg), EXAMPLE 1B (646 mg), and
potassium phosphate tribasic (558 mg) were added to
1,2-dimethoxyethane (10 mL). The solution was degassed under vacuum
and flushed with nitrogen three times.
Tris(dibenzylideneacetone)dipalladium(O) (51.6 mg) and
2-(di-tert-butylphosphino)biphenyl (67.2 mg) were added and the
solution was heated to 80.degree. C. for 16 hours. The solution was
cooled, filtered, concentrated, and purified by flash column
chromatography on silica gel with 30% ethyl acetate in hexanes.
Example 77B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(hydroxymethyl)benz-
oic acid
EXAMPLE 77A (256 mg) and lithium hydroxide monohydrate (154 mg)
were added to 1,4-dioxane (4 mL) and water (1 mL). The solution was
heated to 65.degree. C. for 16 hours, cooled, concentrated under
vacuum, and purified by flash column chromatography on silica gel
with ethyl acetate. The solution was subsequently dried with
anhydrous sodium sulfate to afford crude product of sufficient
purity for subsequent use.
Example 77C
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(hydroxymeth-
yl)benzoate
Trimethylsilyldiazomethane (2M solution in diethyl ether, 0.214 mL)
was added to EXAMPLE 77B (170 mg) dissolved in ethyl acetate (2 mL)
and methanol (2 mL). The solution was mixed for 5 minutes after
which the solvent was removed under vacuum to afford crude product
of sufficient purity for subsequent use.
Example 77D
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenoxymeth-
yl)benzoate
Triphenylphosphine (93 mg) was added to tetrahydrofuran (3 mL) and
cooled to 0.degree. C. Diethylazodicarboxylate (40% solution, 0.161
mL) was added, and the solution was stirred at 0.degree. C. for 15
minutes. Phenol (33.3 mg) and EXAMPLE 77C (145 mg) were added, and
the solution was allowed to warm to room temperature and mix for 16
hours. The solution was concentrated on vacuum and purified by
flash column chromatography on silica gel with 30% ethyl acetate
(hexanes) increasing to 50% ethyl acetate (hexanes).
Example 77E
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenoxymethyl)benz-
oic acid
This example was prepared by substituting EXAMPLE 77D for EXAMPLE
77A in EXAMPLE 77B.
Example 77F
This example was prepared by substituting EXAMPLE 77E for EXAMPLE
1E in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.52 (m, 2H), 7.88 (dd, 1H), 7.84 (d, 1H), 7.50 (m, 2H),
7.48 (s, 3H), 7.37 (m, 2H), 7.26-7.10 (m, 4H), 7.01 (s, 1H), 6.87
(t, 1H), 6.83-6.75 (m, 3H), 5.22 (broad s, 2H), 3.84 (dd, 2H),
3.41-3.10 (m, 10H), 2.39 (broad s, 4H), 1.89 (m, 1H), 1.60 (m, 2H),
1.32-1.18 (m, 2H).
Example 78
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morph-
olin-4-ylpropyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide
Example 78A
N-(4-sulfamoylphenyl)acrylamide
4-aminobenzenesulfonamide (1.00 g) and pyridine (1.41 mL) were
added to 1,4-dioxane (30 mL). Acryloyl chloride (0.49 mL) was added
dropwise and the solution was stirred for 3 hours at room
temperature. 1M HCl was added, and the solution extracted with
ethyl acetate. The extracts were dried using brine and anhydrous
sodium sulfate and the solvent was removed to afford crude product
of sufficient purity for subsequent use.
Example 78B
3-morpholino-N-(4-sulfamoylphenyl)propanamide
EXAMPLE 78A (359 mg) and morpholine (1.38 mL) were added to
acetonitrile (10 mL) and N,N-dimethylformamide (1 mL) and mixed at
room temperature for 16 hours.
The solution was concentrated on vacuum, and purified by flash
column chromatography on silica gel with 5% methanol in
dichloromethane.
Example 78C
4-(3-morpholinopropylamino)benzenesulfonamide
EXAMPLE 78B (268 mg) was added to tetrahydrofuran (4 mL). Borane
(1M in tetrahydrofuran, 4.28 mL) was added slowly, and the solution
was mixed at room temperature for 16 hours. The reaction was
quenched slowly with methanol. N,N-diisopropylethylamine resin
(3.42 mmol amine) was added and the solution was mixed at room
temperature for 15 minutes. The solution was filtered, concentrated
on vacuum, and purified by flash column chromatography on silica
gel with 10% methanol in ethyl acetate.
Example 78D
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morph-
olin-4-ylpropyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 78C for EXAMPLE
1F in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 10.98 (broad s, 1H), 7.51-7.44 (m, 9H), 7.40-7.31 (m, 3H),
7.26-7.21 (m, 1H), 7.13 (tt, 1H), 6.94 (dd, 2H), 6.75 (dd, 1H),
6.66 (t, 1H), 6.54 (d, 2H), 6.32 (d, 1H), 3.57 (t, 4H), 3.35 (m,
2H), 3.16-3.04 (m, 6H), 2.35 (m, 10H), 1.60 (m, 2H).
Example 79
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(pyridin-3-yloxy)-
benzamide
Example 79A
methyl 4-bromo-2-fluorobenzoate
4-Bromo-2-fluorobenzoic acid (5.00 g) was added to ethyl acetate
(35 mL) and methanol (35 mL). Trimethylsilyldiazomethane (2M
solution in diethyl ether, 12.56 mL) was added slowly and the
solution was mixed at room temperature for 30 minutes. The solvent
was removed under vacuum, and the crude material was dissolved in
ethyl acetate. The solution was extracted with 0.5M sodium
hydroxide and dried with brine then anhydrous sodium sulfate. After
filtration, the solvent was removed under vacuum to afford crude
product of sufficient purity for subsequent use.
Example 79B
methyl 4-bromo-2-(pyridin-3-yloxy)benzoate
EXAMPLE 79A (500 mg), pyridine-3-ol (204 mg), and potassium
carbonate (385 mg) were added to N,N-dimethylacetamide (18 mL) and
the mixture was heated to 145.degree. C. for 2 hours and then at
130.degree. C. for 16 hours. The solution was cooled, added to
water (100 mL), extracted with 70% ethyl acetate in hexanes, and
dried with anhydrous sodium sulfate. After filtration, the solution
was concentrated under vacuum and purified by flash column
chromatography on silica gel with 50-70% ethyl acetate in
hexanes.
Example 79C
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(pyridin-3-y-
loxy)benzoate
EXAMPLE 79B (367 mg), EXAMPLE 1B (410 mg), and potassium phosphate
tribasic (379 mg) were added to 1,2-dimethoxyethane (6 mL). The
solution was degassed under vacuum and flushed with nitrogen three
times.
Tris(dibenzylideneacetone)dipalladium(O) (32.7 mg) and
2-(di-tert-butylphosphino)biphenyl (42.6 mg) were added and the
solution was heated to 80.degree. C. for 16 hours. The solution was
cooled, filtered, concentrated, and purified by flash column
chromatography on silica gel with 50-70% ethyl acetate in
hexanes.
Example 79D
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(pyridin-3-yloxy)be-
nzoic acid
This example was prepared by substituting EXAMPLE 79C for EXAMPLE
1D in EXAMPLE 1E.
Example 79E
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(pyridin-3-yloxy)-
benzamide
This example was prepared by substituting EXAMPLE 79D for EXAMPLE
1E in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.72 (broad s, 1H), 8.64 (t, 1H), 8.46 (d, 1H), 8.15 (t,
2H), 7.75 (dd, 1H), 7.52-7.44 (m, 6H), 7.37 (m, 2H), 7.26-7.10 (m,
4H), 6.79 (dd, 1H), 6.50 (d, 1H), 3.87 (dd, 2H), 3.40 (s, 2H),
3.38-3.24 (m, 4H), 3.19 (broad s, 4H), 2.37 (broad s, 4H), 1.92 (m,
1H), 1.65 (d, 2H), 1.28 (m, 2H).
Example 80
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(pyridin-3-yl-
oxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamid-
e
This example was prepared by substituting EXAMPLE 79D for EXAMPLE
1E and EXAMPLE 2A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.34 (s, 1H), 8.27 (dd,
2H), 7.51-7.44 (m, 8H), 7.41-7.29 (m, 3H), 7.27-7.19 (m, 2H), 6.78
(dd, 1H), 6.72 (t, 1H), 6.56 (d, 2H), 6.44 (d, 1H), 3.86 (dd, 2H),
3.36 (s, 2H), 3.29-3.22 (m, 2H), 3.16 (m, 4H), 2.96 (t, 2H), 2.34
(m, 4H), 1.77 (m, 1H), 1.66 (d, 2H), 1.21 (m, 2H).
Example 81
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-({(1R)-3--
(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl-
}-2-phenoxybenzamide
Example 81A
(R)-tert-butyl
3-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-hydroxybutanoate
Fmoc-D-Asp(OtBu)-OH (9.0 g) and N,N-diisopropylethylamine (4.6 mL)
were added to tetrahydrofuran (100 mL) and cooled to -40.degree. C.
Isobutyl chloroformate (3.1 mL) was added, and the solution was
gradually warmed to 0.degree. C. over 30 minutes. The solution was
cooled to -20.degree. C., and to it was carefully added sodium
borohydride (1.64 g, 43.6 mmol) and methanol (10 mL). The solution
was gradually warmed to room temperature over two hours, diluted
with ethyl acetate (200 mL), washed with water (100 mL) and brine
(50 mL), dried with anhydrous magnesium sulfate, filtered, and
concentrated to afford crude product of sufficient purity for
subsequent use.
Example 81B
(R)-tert-butyl
3-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-(phenylthio)butanoate
Tri-n-butylphosphine (90 .mu.L) and
1,1'-(azodicarbonyl)dipiperidine (91 mg) were added to
tetrahydrofuran (4 mL), treated with EXAMPLE 81A (90 mg) and
thiophenol (21 mg), and stirred at room temperature for 18 hours.
The solution was concentrated and purified by flash column
chromatography on silica gel with 50% ethyl acetate in hexanes.
Example 81C
(R)-tert-butyl
3-(2-nitro-4-sulfamoylphenylamino)-4-(phenylthio)butanoate
EXAMPLE 81B (600 mg), 4-fluoro-3-nitrobenzenesulfonamide (298 mg),
and N,N-diisopropylethylamine (3 mL) were added to
N,N-dimethylformamide (3 mL) and stirred at 60.degree. C. for 12
hours. The reaction mixture was diluted with ethyl acetate (100
mL), washed with water (45 mL) and brine (10 mL), dried with
anhydrous magnesium sulfate, filtered, and concentrated. The
residue was purified by flash column chromatography on silica gel
with 30% ethyl acetate in dichloromethane.
Example 81D
(R)-3-(2-nitro-4-sulfamoylphenylamino)-4-(phenylthio)butanoic
acid
EXAMPLE 81C (468 mg) and 4 M HCl in 1,4-dioxane (10 mL) were
stirred at 50.degree. C. for 5 hours. The solution was concentrated
to give the crude product of sufficient purity for subsequent
use.
Example 81E
(R)--N,N-dimethyl-3-(2-nitro-4-sulfamoylphenylamino)-4-(phenylthio)butanam-
ide
This example was prepared by substituting EXAMPLE 81D for EXAMPLE
1E and dimethylamine (2M in tetrahydrofuran) for EXAMPLE 1F in
EXAMPLE 1G.
Example 81F
(R)-4-(4-(dimethylamino)-1-(phenylthio)butan-2-ylamino)-3-nitrobenzenesulf-
onamide
To EXAMPLE 81E (4.06 g) was added borane (1 M in tetrahydrofuran,
20.0 mL). The solution was stirred at room temperature for 16
hours. The reaction was quenched slowly with methanol (5.0 mL) and
concentrated aqueous HCl (2.0 mL) was added. The solution was
stirred at 80.degree. C. for three hours, cooled to room
temperature, carefully basified with 4 M sodium carbonate, diluted
with ethyl acetate (150 mL), washed with water (50 mL) and brine
(10 mL), dried with anhydrous magnesium sulfate, and filtered. The
solution was concentrated and purified by flash column
chromatography on silica gel with 20% methanol in
dichloromethane.
Example 81G
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-({(1R)-3--
(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl-
}-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 81F for EXAMPLE
1F in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.33 (d, 1H), 8.28 (d, 1H), 7.61 (dd, 2H), 7.50-7.43 (m,
4H), 7.37-7.14 (m, 11H), 6.90 (t, 1H), 6.84 (d, 1H), 6.71 (d, 2H),
6.70 (dd, 1H), 6.32 (d, 1H), 4.06 (m, 1H), 3.36 (s, 2H), 3.33-3.30
(m, 2H), 3.08 (t, 4H), 2.86 (m, 2H), 2.53 (s, 6H), 2.35 (t, 4H),
2.04 (m, 2H).
Example 82
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(pyridin-4-yloxy)-
benzamide
Example 82A
methyl 4-bromo-2-(pyridin-4-yloxy)benzoate
EXAMPLE 79A (800 mg), pyridine-4-ol (359 mg), and potassium
carbonate (617 mg) were added to N,N-dimethylacetamide (20 mL) and
the mixture was heated to 125.degree. C. for 16 hours. The solution
was concentrated on vacuum at 48.degree. C. and purified by flash
column chromatography on silica gel with 20% methanol in
dichloromethane.
Example 82B
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(pyridin-4-y-
loxy)benzoate
This example was prepared by substituting EXAMPLE 82A for EXAMPLE
79B in EXAMPLE 79C.
Example 82C
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(pyridin-4-yloxy)be-
nzoic acid
This example was prepared by substituting EXAMPLE 82B for EXAMPLE
1D in EXAMPLE 1E.
Example 82D
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(pyridin-4-yloxy)-
benzamide
This example was prepared by substituting EXAMPLE 82C for EXAMPLE
1E in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.40 (t, 1H), 8.37 (d, 1H), 7.76 (dd, 1H), 7.65 (d, 1H),
7.54-7.48 (m, 1H), 7.47 (s, 3H), 7.42-7.35 (m, 5H), 7.27-7.23 (m,
1H), 7.06 (dd, 1H), 6.92 (dd, 1H), 6.88 (d, 1H), 5.91 (d, 2H), 3.85
(dd, 2H), 3.39 (s, 2H), 3.34-3.25 (m, 4H), 3.19 (broad, s, 4H),
2.39 (broad s, 4H), 1.92 (m, 1H), 1.65 (d, 2H), 1.27 (m, 2H).
Example 83
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morph-
olin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(pyridin-3-yloxy)benzamid-
e
This example was prepared by substituting EXAMPLE 79D for EXAMPLE
1E and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 8.73 (t, 1H), 8.43 (d, 1H),
8.12 (t, 2H), 7.73 (dd, 1H), 7.55 (d, 1H), 7.51-7.44 (m, 4H), 7.37
(m, 2H), 7.25-7.17 (m, 3H), 7.07 (d, 2H), 6.78 (dd, 1H), 6.47 (d,
1H), 3.65 (t, 4H), 3.47 (q, 2H), 3.38 (s, 2H), 3.28 (m, 2H), 3.17
(br s, 4H), 2.57 (br s, 4H), 2.36 (br s, 4H), 1.84 (m, 2H).
Example 84
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morph-
olin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(pyridin-4-yloxy)benzamid-
e
This example was prepared by substituting EXAMPLE 82C for EXAMPLE
1E and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 8.55 (t, 1H), 8.37 (d, 1H),
7.77 (dd, 1H), 7.65 (d, 1H), 7.54-7.43 (m, 5H), 7.42-7.32 (m, 4H),
7.26-7.22 (m, 1H), 7.01 (d, 1H), 6.91 (dd, 1H), 6.66 (d, 1H), 5.90
(d, 2H), 3.60 (t, 4H), 3.43 (q, 2H), 3.39 (s, 2H), 3.18 (br s, 4H),
2.38 (m, 10H), 1.80 (t, 2H).
Example 85
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[2-(4-me-
thylpiperazin-1-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamide
Example 85A
4-(2-(4-methylpiperazin-1-yl)ethylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting
2-(4-methylpiperazin-1-yl)ethanamine for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 85B
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[2-(4-me-
thylpiperazin-1-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 85A for EXAMPLE
1F in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.61 (t, 1H), 8.40 (d, 1H), 7.72 (dd, 1H), 7.57 (d, 1H),
7.51-7.44 (m, 5H), 7.36 (m, 2H), 7.26-7.15 (m, 3H), 6.95 (t, 2H),
6.75 (dd, 2H), 6.71 (dd, 1H), 6.34 (d, 1H), 3.45 (q, 2H), 3.36 (s,
2H), 3.34 (m, 2H), 3.10 (t, 4H), 2.79 (broad s, 4H), 2.68 (t, 2H),
2.60 (broad s, 2H), 2.49 (s, 3H), 2.35 (t, 4H).
Example 86
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(4-me-
thylpiperazin-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamid-
e
Example 86A
4-(3-(4-methylpiperazin-1-yl)propylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting
3-(4-methylpiperazin-1-yl)propan-1-amine for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 86B
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(4-me-
thylpiperazin-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamid-
e
This example was prepared by substituting EXAMPLE 86A for EXAMPLE
1F in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.57 (t, 1H), 8.38 (d, 1H), 7.71 (dd, 1H), 7.59 (d, 1H),
7.50-7.44 (m, 5H), 7.36 (m, 2H), 7.27-7.15 (m, 3H), 6.98 (d, 2H),
6.91 (t, 1H), 6.73 (dd, 2H), 6.70 (dd, 2H), 6.33 (d, 1H), 3.43 (q,
2H), 3.36 (s, 2H), 3.34 (m, 2H), 3.09 (t, 4H), 2.82 (broad s, 4H),
2.56 (broad s, 2H), 2.49 (s, 3H), 2.35 (t, 4H), 1.79 (t, 2H).
Example 87
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[[3-(dime-
thylamino)propyl](methyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide
Example 87A
4-((3-(dimethylamino)propyl)(methyl)amino)-3-nitrobenzenesulfonamide
This example was prepared by substituting
N.sup.1,N,N.sup.3-trimethylpropane-1,3-diamine for
3-(pyrrolidin-1-yl)propan-1-amine in EXAMPLE 68F.
Example 87B
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[[3-(dime-
thylamino)propyl](methyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 87A for EXAMPLE
1F in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.01 (d, 1H), 7.68 (dd, 1H), 7.63 (d, 1H), 7.51-7.44 (m,
5H), 7.36 (m, 2H), 7.26-7.13 (m, 3H), 6.93 (t, 1H), 6.83 (m, 1H),
6.74 (dd, 2H), 6.69 (dd, 1H), 6.32 (d, 1H), 3.46 (q, 2H), 3.36 (s,
2H), 3.08 (t, 4H), 2.83 (t, 2H), 2.77 (s, 3H), 2.60 (s, 6H), 2.36
(t, 4H), 1.86 (m, 2H).
Example 88
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[(1-meth-
ylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamide
Example 88A
4-((1-methylpiperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting
(1-methylpiperidin-4-yl)methanamine for
3-(pyrrolidin-1-yl)propan-1-amine in EXAMPLE 68F.
Example 88B
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[(1-meth-
ylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 88A for EXAMPLE
1F in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.44 (t, 1H), 8.35 (d, 1H), 7.79 (dd, 1H), 7.62 (d, 1H),
7.51-7.45 (m, 5H), 7.36 (m, 2H), 7.25-7.14 (m, 3H), 6.99 (d, 1H),
6.89 (t, 1H), 6.71 (d, 2H), 6.68 (dd, 1H), 6.31 (d, 1H), 3.36 (s,
2H), 3.34 (m, 4H), 3.07 (t, 4H), 2.73 (m, 2H), 2.62 (s, 3H), 2.36
(t, 4H), 1.90-1.82 (m, 3H), 1.47-1.31 (m, 2H).
Example 89
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(1-methy-
lpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 21A for EXAMPLE
1F in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.38 (t, 1H), 8.09 (d, 1H), 7.73 (m, 1H), 7.59 (d, 1H),
7.52-7.44 (m, 5H), 7.36 (m, 2H), 7.26-7.22 (m, 1H), 7.17 (t, 1H),
7.05 (d, 1H), 6.90 (t, 1H), 6.83 (m, 1H), 6.72 (d, 2H), 6.70 (dd,
1H), 6.33 (d, 1H), 3.36 (q, 2H), 3.36 (s, 2H), 3.24-3.12 (m, 2H),
3.09 (t, 4H), 2.80 (m, 1H), 2.59 (s, 3H), 2.36 (t, 4H), 2.08 (m,
2H), 1.77 (m, 2H).
Example 90
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-cyano-4-{-
[3-(dimethylamino)propyl]amino}phenyl)sulfonyl]-2-phenoxybenzamide
Example 90A
3-cyano-4-fluorobenzenesulfonamide
Concentrated ammonium hydroxide (28% solution in water, 3.17 mL)
was cooled to 0.degree. C. and 3-cyano-4-fluorobenzene-1-sulfonyl
chloride (1.00 g) was added. The solution was mixed at 0.degree. C.
for four minutes. 4M HCl (10 mL) was added slowly and the solution
was extracted with ethyl acetate. The extract was dried on brine
and anhydrous sodium sulfate and the solvent removed under
vacuum.
Example 90B
3-cyano-4-(3-(dimethylamino)propylamino)benzenesulfonamide
This example was prepared by substituting EXAMPLE 90A for
4-chloro-3-nitrobenzenesulfonamide and
N.sup.1,N.sup.1-dimethylpropane-1,3-diamine for
3-(pyrrolidin-1-yl)propan-1-amine in EXAMPLE 68F.
Example 90C
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-cyano-4-{-
[3-(dimethylamino)propyl]amino}phenyl)sulfonyl]-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 90B for EXAMPLE
1F in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 7.67 (s, 1H), 7.66 (dd, 1H), 7.59 (d, 1H), 7.51-7.44 (m,
5H), 7.36 (m, 2H), 7.28-7.20 (m, 3H), 6.98 (t, 2H), 6.77 (dd, 2H),
6.70 (d, 2H), 6.33 (d, 1H), 3.36 (s, 2H), 3.27 (q, 2H), 3.09 (t,
4H), 2.82 (t, 2H), 2.54 (s, 6H), 2.35 (t, 4H), 1.82 (m, 2H).
Example 91
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 68F for EXAMPLE
1F in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.49 (t, 1H), 8.37 (d, 1H), 7.72 (dd, 1H), 7.62 (d, 1H),
7.50-7.43 (m, 5H), 7.35 (m, 2H), 7.26-7.14 (m, 3H), 6.97 (d, 1H),
6.90 (t, 1H), 6.72 (d, 2H), 6.69 (dd, 1H), 6.31 (d, 1H), 3.47 (q,
2H), 3.36 (s, 2H), 3.20 (m, 2H), 3.07 (broad s, 8H), 2.35 (broad s,
4H), 1.95-1.83 (m, 6H).
Example 92
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-{[3-(dime-
thylamino)propyl]amino}-3-(trifluoromethyl)phenyl]sulfonyl}-2-phenoxybenza-
mide
Example 92A
4-fluoro-3-(trifluoromethyl)benzenesulfonamide
This example was prepared by substituting
4-fluoro-3-(trifluoromethyl)benzene-1-sulfonyl chloride for
3-cyano-4-fluorobenzene-1-sulfonyl chloride in EXAMPLE 90A.
Example 92B
4-(3-(dimethylamino)propylamino)-3-(trifluoromethyl)benzenesulfonamide
This example was prepared by substituting EXAMPLE 92A for
4-fluoro-3-nitrobenzenesulfonamide and
N.sup.1,N.sup.1-dimethylpropane-1,3-diamine for
tetrahydropyran-4-yl)methylamine in EXAMPLE 1F
Example 92C
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-{[3-(dime-
thylamino)propyl]amino}-3-(trifluoromethyl)phenyl]sulfonyl}-2-phenoxybenza-
mide
This example was prepared by substituting EXAMPLE 92B for EXAMPLE
1F in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 7.77 (s, 1H), 7.68 (dd, 1H), 7.57 (d, 1H), 7.51-7.45 (m,
5H), 7.36 (m, 2H), 7.29-7.21 (m, 3H), 6.99 (t, 1H), 6.82-6.68 (m,
5H), 6.32 (d, 1H), 3.36 (s, 2H), 3.28 (q, 2H), 3.09 (t, 4H), 2.73
(m, 2H), 2.48 (s, 6H), 2.35 (t, 4H), 1.79 (m, 2H).
Example 93
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-({3-[isop-
ropyl(methyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-phenoxybenzamid-
e
Example 93A
tert-butyl
methyl(3-(2-nitro-4-sulfamoylphenylamino)propyl)carbamate
This example was prepared by substituting tert-butyl
3-aminopropyl(methyl)carbamate for
3-(pyrrolidin-1-yl)propan-1-amine in EXAMPLE 68F.
Example 93B
tert-butyl
3-(4-(N-(4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-
-phenoxybenzoyl)sulfamoyl)-2-nitrophenylamino)propyl(methyl)carbamate
This example was prepared by substituting EXAMPLE 93A for EXAMPLE
1F in EXAMPLE 1G.
Example 93C
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-N-(4-(3-(methylamino)-
propylamino)-3-nitrophenylsulfonyl)-2-phenoxybenzamide
EXAMPLE 93B (112 mg) and triethylsilane (0.082 mL) were added to
dichloromethane (2 mL). Trifluoroacetic acid (0.198 mL) was added,
the solution stirred at room temperature for one hour, and the
solvent removed under vacuum.
Example 93D
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-({3-[isop-
ropyl(methyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-phenoxybenzamid-
e
EXAMPLE 93C (128 mg), acetone (0.014 mL), and sodium
cyanoborohydride resin (2.15 mmol/g, 66 mg) were added to
tetrahydrofuran (0.9 mL) and acetic acid (0.3 mL), and the solution
was stirred at room temperature for 16 hours. More acetone (0.014
mL), and sodium cyanoborohydride resin (66 mg) were added, and the
solution was stirred for 24 hours. The solution was purified by
flash column chromatography on silica gel with 1% acetic acid and
10% methanol in dichloromethane. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.93 (broad s, 3H), 8.53 (broad
s, 1H), 8.40 (d. 1H), 7.75 (dd, 1H), 7.60 (d, 1H), 7.51-7.45 (m,
5H), 7.36 (m, 2H), 7.25-7.16 (m, 3H), 7.02 (d, 1H), 6.92 (t, 1H),
6.74 (d, 2H), 6.70 (dd, 1H), 6.32 (d, 1H), 3.47 (m, 4H), 3.36 (s,
2H), 3.09 (t, 4H), 3.01 (broad s, 2H), 2.58 (s, 3H), 2.35 (t, 4H),
1.94 (m, 1H), 1.18-1.14 (m, 6H).
Example 94
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[3-(dimet-
hylamino)propoxy]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide
Example 94A
4-(3-(dimethylamino)propoxy)-3-nitrobenzenesulfonamide
Triphenylphosphine (1.398 g) was added to tetrahydrofuran (20 mL)
and cooled to 0.degree. C. Diethylazodicarboxylate (40% solution,
2.428 mL) was added, and the solution was stirred for at 0.degree.
C. for 15 minutes. 4-Hydroxy-3-nitrobenzenesulfonamide (1.163 g)
and 3-(dimethylamine)propan-1-ol (0.567 mL) were added, and the
solution was allowed to warm to room temperature and stir for 16
hours. Solvent was removed under vacuum and the material
recrystallized using 20% methanol (dichloromethane). The
recrystallized solid was washed with dichloromethane, dissolved in
methanol/dichloromethane, treated with triethylamine (0.13 mL,
0.924 mmol), and purified by flash column chromatography on silica
gel with 10-20% methanol in dichloromethane.
Example 94B
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[3-(dimet-
hylamino)propoxy]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 94A for EXAMPLE
1F in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.06 (d, 1H), 7.84 (dd, 1H), 7.65 (d, 1H), 7.52-7.45 (m,
5H), 7.36 (m, 2H), 7.26-7.22 (m, 2H), 7.18 (td, 2H), 6.89 (t, 1H),
6.69 (d, 1H), 6.68 (d, 2H), 6.32 (d, 1H), 4.25 (t, 2H), 3.36 (s,
2H), 3.13 (t, 2H), 3.08 (t, 4H), 2.75 (s, 6H), 2.36 (t, 4H), 2.11
(m, 2H).
Example 95
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(4-methylpiperazin-1-yl)ethyl]amino}--
3-nitrophenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 85A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.10 (s, 1H), 8.67 (t,
1H), 8.53 (d, 1H), 7.78 (dd, 1H), 7.52 (d, 1H), 7.39-7.31 (m, 4H),
7.08-7.02 (m, 3H), 6.94 (d, 1H), 6.80 (dd, 1H), 6.61 (dd, 1H), 6.36
(t, 1H), 6.14 (d, 1H), 3.42 (q, 2H), 2.99 (t, 4H), 2.71 (s, 2H),
2.70-2.48 (m, 10H), 2.39 (s, 3H), 2.16 (m, 6H), 1.95 (s, 2H), 1.38
(t, 2H), 0.92 (s, 6H).
Example 96
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[3-(4-methylpiperazin-1-yl)propyl]amino}-
-3-nitrophenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 86A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.09 (s, 1H), 8.62 (t,
1H), 8.51 (d, 1H), 7.76 (dd, 1H), 7.53 (d, 1H), 7.38-7.31 (m, 4H),
7.05 (s, 1H), 7.02 (d, 2H), 6.96 (d, 1H), 6.79 (dd, 1H), 6.60 (dd,
1H), 6.35 (t, 1H), 6.14 (d, 1H), 3.40 (q, 2H), 2.98 (t, 4H), 2.71
(s, 2H), 2.67 (broad s, 4H), 2.55-2.40 (m, 6H), 2.39 (s, 3H), 2.16
(m, 6H), 1.95 (s, 2H), 1.77 (m, 2H), 1.38 (t, 2H), 0.92 (s,
6H).
Example 97
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]p-
henyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 68F for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.06 (s, 1H), 8.58 (t,
1H), 8.49 (d, 1H), 7.77 (dd, 1H), 7.54 (d, 1H), 7.36-7.31 (m, 4H),
7.06-7.01 (m, 3H), 6.95 (d, 1H), 6.76 (dd, 1H), 6.57 (dd, 1H), 6.35
(t, 1H), 6.14 (d, 1H), 3.44 (q, 2H), 2.97 (broad s, 10H), 2.71 (s,
2H), 2.16 (m, 6H), 1.95 (s, 2H), 1.90-1.80 (m, 6H), 1.38 (t, 2H),
0.92 (s, 6H).
Example 98
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.08 (s, 1H), 8.51 (d,
1H), 8.13 (d, 1H), 7.78 (dd, 1H), 7.52 (d, 1H), 7.37-7.31 (m, 4H),
7.06-7.00 (m, 4H), 6.79 (dd, 1H), 6.59 (dd, 1H), 6.35 (t, 1H), 6.14
(d, 1H), 3.73 (m, 1H), 3.05-2.95 (m, 6H), 2.71 (s, 2H), 2.60 (m,
2H), 2.48 (s, 3H), 2.16 (m, 6H), 2.01 (m, 2H), 1.95 (s, 2H), 1.70
(m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 99
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[3-(4-methylpiperazin-1-yl)propyl]amino}-
-3-nitrophenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 86A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.16 (s, 1H), 8.59 (t,
1H), 8.45 (d, 1H), 7.72 (dd, 1H), 7.55 (d, 1H), 7.34 (d, 2H), 7.23
(t, 1H), 7.12 (d, 1H), 7.02 (d, 2H), 6.95 (d, 1H), 6.94 (t, 1H),
6.64 (dd, 1H), 6.35 (d, 1H), 6.23 (m, 2H), 3.41 (q, 2H), 2.98 (t,
4H), 2.71 (broad s, 6H), 2.52-2.42 (m, 6H), 2.41 (s, 3H), 2.15 (m,
6H), 1.95 (s, 2H), 1.77 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 100
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[3-(dimethylamino)propoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-
-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 94A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.03 (s, 1H), 8.23 (d,
1H), 7.91 (dd, 1H), 7.56 (d, 1H), 7.36-7.29 (m, 4H), 7.19 (d, 1H),
7.05 (d, 2H), 6.97 (s, 1H), 6.73 (dd, 1H), 6.57 (dd, 1H), 6.33 (t,
1H), 6.15 (d, 1H), 4.23 (t, 2H), 3.04 (m, 2H), 2.96 (t, 4H), 2.72
(s, 2H), 2.67 (s, 6H), 2.22-2.02 (m, 8H), 1.95 (s, 2H), 1.38 (t,
2H), 0.92 (s, 6H).
Example 101
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(4-methylpiperazin-1-yl)ethyl]amino}--
3-nitrophenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 85A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.18 (s, 1H), 8.64 (t,
1H), 8.47 (d, 1H), 7.73 (dd, 2H), 7.56 (d, 1H), 7.34 (d, 2H), 7.24
(t, 1H), 7.04 (d, 2H), 6.96 (d, 1H), 6.94 (d, 1H), 6.65 (dd, 1H),
6.37 (d, 1H), 6.23 (m, 2H), 3.43 (q, 2H), 2.99 (t, 4H), 2.71 (s,
2H), 2.65 (m, 6H), 2.56 (m, 4H), 2.42 (s, 3H), 2.15 (m, 6H), 1.95
(s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 102
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]p-
henyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 68F for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.14 (s, 1H), 8.54 (t,
1H), 8.44 (d, 1H), 7.76 (dd, 1H), 7.59 (d, 1H), 7.34 (d, 2H), 7.22
(t, 1H), 7.10 (d, 1H), 7.05 (d, 2H), 6.98-6.89 (m, 2H), 6.62 (dd,
1H), 6.33 (d, 1H), 6.23 (t, 1H), 6.21 (d, 1H), 3.44 (q, 2H),
3.10-2.91 (m, 10H), 2.71 (s, 2H), 2.16 (m, 6H), 1.95 (s, 2H),
1.92-1.79 (m, 6H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 103
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.14 (s, 1H), 8.44 (d,
1H), 8.11 (d, 1H), 7.75 (dd, 1H), 7.56 (d, 1H), 7.34 (d, 2H), 7.23
(t, 1H), 7.11 (d, 1H), 7.04 (d, 2H), 7.03 (d, 1H), 6.93 (t, 1H),
6.64 (dd, 1H), 6.34 (d, 1H), 6.22 (m, 2H), 3.73 (m, 1H), 3.08-2.93
(m, 6H), 2.71 (s, 2H), 2.70-2.56 (m, 2H), 2.48 (s, 3H), 2.16 (m,
6H), 2.02 (m, 2H), 1.95 (s, 2H), 1.70 (m, 2H), 1.38 (t, 2H), 0.92
(s, 6H).
Example 104
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-
-nitrophenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 88A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 10.99 (s, 1H), 8.39 (d,
1H), 8.32 (t, 1H), 7.65 (dd, 1H), 7.54 (d, 1H), 7.34 (d, 2H),
7.30-7.26 (m, 2H), 7.05 (d, 2H), 6.92 (d, 1H), 6.81 (d, 1H), 6.70
(dd, 1H), 6.53 (dd, 1H), 6.30 (t, 1H), 6.15 (d, 1H), 3.28-3.19 (m,
2H), 2.93 (t, 4H), 2.83 (m, 2H), 2.71 (s, 2H), 2.68-2.50 (m, 2H),
2.54 (s, 3H), 2.24-2.10 (m, 6H), 1.95 (broad s, 2H), 1.68 (d, 2H),
1.59 (m, 1H), 1.38 (t, 2H), 1.32-1.17 (m, 2H), 0.92 (s, 6H).
Example 105
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-
-nitrophenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 88A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.11 (s, 1H), 8.44 (t,
1H), 8.41 (d, 1H), 7.74 (dd, 1H), 7.59 (d, 1H), 7.34 (d, 2H), 7.21
(t, 1H), 7.11-7.02 (m, 3H), 6.98-6.90 (m, 2H), 6.61 (dd, 1H), 6.31
(d, 1H), 6.23 (t, 1H), 6.20 (d, 1H), 3.20 (m, 2H), 2.95 (t, 4H),
2.71 (s, 2H), 2.62-2.49 (m, 4H), 2.55 (s, 3H), 2.16 (m, 6H), 1.95
(s, 2H), 1.86-1.78 (m, 3H), 1.42-1.31 (m, 4H), 0.92 (s, 6H).
Example 106
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[3-(dimethylamino)propoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-
-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 94A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.10 (s, 1H), 8.16 (d,
1H), 7.90 (dd, 1H), 7.61 (d, 1H), 7.35 (d, 2H), 7.24-7.19 (m, 2H),
7.10-7.01 (m, 3H), 6.91 (t, 1H), 6.60 (dd, 1H), 6.28 (d, 1H), 6.23
(t, 1H), 6.20 (d, 1H), 4.23 (t, 2H), 3.03 (t, 2H), 2.95 (t, 4H),
2.72 (s, 2H), 2.67 (s, 6H), 2.17 (m, 6H), 2.07 (m, 2H), 1.95 (s,
2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 107
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(4-methylpiperazin-1-yl)-3-nitrophenyl]su-
lfonyl}benzamide
Example 107A
4-(4-methylpiperazin-1-yl)-3-nitrobenzenesulfonamide
This example was prepared by substituting 1-methylpiperazine for
3-(pyrrolidin-1-yl)propan-1-amine in EXAMPLE 68F.
Example 107B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(4-methylpiperazin-1-yl)-3-nitrophenyl]su-
lfonyl}benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 107A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.21 (s, 1H), 8.18 (d,
1H), 7.77 (dd, 1H), 7.57 (d, 1H), 7.34 (d, 2H), 7.26 (t, 1H), 7.22
(d, 1H), 7.16 (d, 1H), 7.07-7.02 (m, 2H), 6.96 (t, 1H), 6.87 (dd,
1H), 6.39 (d, 1H), 6.25 (m, 2H), 3.16 (m, 4H), 3.01 (t, 4H), 2.73
(s, 2H), 2.66 (broad s, 4H), 2.39 (s, 3H), 2.18 (m, 6H), 1.95 (s,
2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 108
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[1-(2,2,2-trifluoroethyl)piperid-
in-4-yl]amino}phenyl)sulfonyl]benzamide
Example 108A
3-nitro-4-(1-(2,2,2-trifluoroethyl)piperidin-4-ylamino)benzenesulfonamide
4-chloro-3-nitrobenzenesulfonamide (1.300 g),
1-(2,2,2-trifluoroethyl)piperidin-4-amine hydrochloride (1.201 g),
and triethylamine (2.30 mL) were added to 1,4-dioxane (50 mL) and
water (5 mL) and heated at 90.degree. C. for 16 hours. The solution
was concentrated on vacuum and purified by flash column
chromatography on silica gel with ethyl acetate increasing to 5%
methanol in ethyl acetate.
Example 108B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[1-(2,2,2-trifluoroethyl)piperid-
in-4-yl]amino}phenyl)sulfonyl]benzamide
This EXAMPLE was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 108A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.24 (s, 1H), 8.50 (d,
1H), 8.25 (d, 1H), 7.71 (dd, 1H), 7.52 (d, 1H), 7.34 (d, 2H), 7.27
(t, 1H), 7.17 (d, 1H), 7.11 (d, 1H), 7.04 (d, 2H), 6.97 (t, 1H),
6.71 (dd, 1H), 6.43 (d, 1H), 6.28 (d, 1H), 6.24 (t, 1H), 3.68 (m,
1H), 3.23 (q, 2H), 3.06 (broad s, 4H), 2.95-2.87 (m, 2H), 2.78-2.71
(m, 2H), 2.58 (t, 2H), 2.25-2.11 (m, 6H), 1.98-1.85 (m, 4H), 1.64
(m, 2H), 1.39 (t, 2H), 0.92 (s, 6H).
Example 109
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(dimethylamino)-1-methylpiperidin-4-yl]methyl}amino)-3-ni-
trophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide
Example 109A
4-((4-(dimethylamino)-1-methylpiperidin-4-yl)methylamino)-3-nitrobenzenesu-
lfonamide
This example was prepared by substituting
4-(aminomethyl)-N,N,1-trimethylpiperidin-4-amine for
1-(2,2,2-trifluoroethyl)piperidin-4-amine hydrochloride in EXAMPLE
108A.
Example 109B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(dimethylamino)-1-methylpiperidin-4-yl]methyl}amino)-3-ni-
trophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 109A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.06 (s, 1H), 8.56 (broad
s, 1H), 8.50 (d, 1H), 7.81 (dd, 1H), 7.54 (d, 1H), 7.36-7.31 (m,
4H), 7.08-7.02 (m, 4H), 6.77 (dd, 1H), 6.57 (dd, 1H), 6.34 (t, 1H),
6.13 (d, 1H), 3.50 (d, 2H), 3.04 (m, 2H), 2.96 (t, 4H), 2.87 (m,
2H), 2.71 (s, 2H), 2.58 (s, 3H), 2.28 (s 6H), 2.16 (m, 6H) 1.98 (m,
2H) 1.95 (s, 2H), 1.65-1.54 (m, 2H), 1.38 (t, 2H), 0.94 (s,
6H).
Example 110
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(2,3-dihydro--
1,4-benzodioxin-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)am-
ino]phenyl}sulfonyl)benzamide
Example 110A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydro-
benzo[b][1,4]dioxin-5-yloxy)benzoate
This example was prepared by substituting EXAMPLE 34A for EXAMPLE
18E and 2,3-dihydrobenzo[b][1,4]dioxin-5-ol for phenol in EXAMPLE
18F.
Example 110B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydrobenzo[b-
][1,4]dioxin-5-yloxy)benzoic acid
This example was prepared by substituting EXAMPLE 110A for EXAMPLE
1D in EXAMPLE 1E.
Example 110C
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(2,3-dihydro--
1,4-benzodioxin-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)am-
ino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 110B for EXAMPLE
1E in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. ppm 11.40 (s, 1H), 8.65 (t, 1H), 8.55 (d, 1H), 7.83 (dd,
1H), 7.46 (m, 6H), 7.36 (m, 2H), 7.23 (m, 2H), 6.77 (d, 1H), 6.70
(dd, 1H), 6.42 (m, 2H), 6.27 (d, 1H), 4.20 (s, 4H), 3.85 (dd, 2H),
3.37 (m, 4H), 3.25 (m, 2H), 3.13 (m, 4H), 2.35 (m, 4H), 1.90 (m,
1H), 1.62 (dd, 2H), 1.27 (m, 2H).
Example 111
5-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-1,1'-biphenyl-2-car-
boxamide
Example 111A
methyl
5-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)biphenyl-2-carb-
oxylate
EXAMPLE 34A (100 mg, 0.2 mmol) in tetrahydrofuran (1.5 mL) was
treated with phenylboronic acid (36.6 mg, 0.3 mmol),
tris(dibenzylideneacetone)dipalladium(O) (9.2 mg, 0.01 mmol),
tri-tert-butylphosphonium tetrafluoroborate (5.8 mg, 0.02 mmol) and
cesium fluoride (91 mg, 0.6 mmol), flushed with nitrogen and
stirred overnight at ambient temperature. The reaction mixture was
diluted with ethyl acetate, washed with water and brine, dried
(MgSO.sub.4), filtered and concentrated. The concentrate was
purified by column chromatography on silica gel eluting with a
gradient of 0 to 3% methanol in CH.sub.2Cl.sub.2 to give the
product.
Example 111B
5-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)biphenyl-2-carboxylic
acid
This example was prepared by substituting EXAMPLE 111A for EXAMPLE
1D in EXAMPLE 1E.
Example 111C
5-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-1,1'-biphenyl-2-car-
boxamide
This example was prepared by substituting EXAMPLE 111B for EXAMPLE
27G in EXAMPLE 27H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 12.09 (s, 1H), 8.72 (t, 1H),
8.46 (d, 1H), 7.79 (m, 2H), 7.52 (m, 4H), 7.35 (dd, 5H), 7.16 (m,
1H), 7.04 (m, 4H), 6.91 (dd, 1H), 6.78 (m, 1H), 4.39 (m, 1H), 3.88
(m, 3H), 3.42 (m, 4H), 3.27 (m, 4H), 2.96 (m, 4H), 1.95 (m, 1H),
1.67 (m, 2H), 1.31 (m, 2H).
Example 112
5-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dime-
thylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-1,1'-biphenyl-2-carboxamid-
e
This example was prepared by substituting EXAMPLE 111B for EXAMPLE
27G and EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d) .delta. ppm 12.09 (s, 1H), 8.74 (t,
1H), 8.47 (d, 1H), 7.83 (dd, 1H), 7.70 (m, 1H), 7.40 (m, 8H), 7.27
(m, 1H), 7.20 (m, 1H), 7.07 (m, 4H), 6.91 (dd, 1H), 6.77 (m, 1H),
4.39 (m, 1H), 3.87 (m, 1H), 3.55 (m, 4H), 3.26 (m, 2H), 3.16 (m,
4H), 3.03 (m, 2H), 2.80 (m, 6H), 1.98 (m, 2H).
Example 113
4-[4-({4'-chloro-4-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)-2-phenoxybenzamide
Example 113A
methyl 2-phenoxy-4-(piperazin-1-yl)benzoate
This example was made by substituting piperazine for EXAMPLE 1B in
EXAMPLE 1D.
Example 113B
methyl
4-(4-(2-bromo-5-hydroxybenzyl)piperazin-1-yl)-2-phenoxybenzoate
This example was made by substituting 2-bromo-5-hydroxybenzaldehyde
for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 113A for
tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
Example 113C
methyl
4-(4-(2-bromo-5-(2-(dimethylamino)ethoxy)benzyl)piperazin-1-yl)-2-p-
henoxybenzoate
A mixture of EXAMPLE 113B (170 mg), 2-chloro-N,N-dimethylethanamine
hydrochloride salt (80 mg) and cesium carbonate (278 mg) was
suspended in anhydrous N,N-dimethylformamide (3 mL). The reaction
mixture was heated at 50.degree. C. overnight. The reaction mixture
was cooled to room temperature and diluted with ethyl acetate. The
organic phase was washed with water and brine, and dried over
anhydrous Na.sub.2SO.sub.4. The solvent was removed under vacuum to
afford an oily residue which was used in the next step without
further purification.
Example 113D
methyl
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-phenoxybenzoate
This example was made by substituting EXAMPLE 113C for EXAMPLE 68C
and 4-chlorophenylboronic acid for 4-methoxyphenylboronic acid in
EXAMPLE 68D.
Example 113E
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-
-1-yl)-2-phenoxybenzoic acid
This example was made by substituting EXAMPLE 113D for EXAMPLE 1D
in EXAMPLE 1E.
Example 113F
4-[4-({4'-chloro-4-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)-2-phenoxybenzamide
This example was made by substituting EXAMPLE 113E for EXAMPLE 1E
in EXAMPLE 27H. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.69 (br s, 1H), 9.87 (br s, 1H), 8.63 (t, 1H), 8.46 (d,
1H), 7.75 (dd, 1H), 7.50 (m, 3H), 7.34-7.23 (m, 6H), 7.14 (m, 2H),
6.98 (m, 1H), 6.78 (m, 3H), 6.44 (d, 1H), 4.37 (t, 2H), 3.86 (m,
2H), 3.60-3.41 (m, 10H), 3.34 (t, 4H), 3.28 (m, 2H), 2.89 (s, 6H),
1.91 (m, 1H), 1.62 (m, 2H), 1.28 (m, 2H).
Example 114
4-(4-{[4'-chloro-4-(3-piperidin-1-ylpropoxy)-1,1'-biphenyl-2-yl]methyl}pip-
erazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)-2-phenoxybenzamide
Example 114A
methyl
4-(4-(2-bromo-5-(3-(piperidin-1-yl)propoxy)benzyl)piperazin-1-yl)-2-
-phenoxybenzoate
This example was made by substituting 1-(3-chloropropyl)piperidine
hydrochloride salt for 2-chloro-N,N-dimethylethanamine
hydrochloride salt in EXAMPLE 113C.
Example 114B
methyl
4-(4-((4'-chloro-4-(3-(piperidin-1-yl)propoxy)biphenyl-2-yl)methyl)-
piperazin-1-yl)-2-phenoxybenzoate
This example was made by substituting EXAMPLE 114A for EXAMPLE 68C
and 4-chlorophenylboronic acid for 4-methoxyphenylboronic acid in
EXAMPLE 68D.
Example 114C
4-(4-((4'-chloro-4-(3-(piperidin-1-yl)propoxy)biphenyl-2-yl)methyl)piperaz-
in-1-yl)-2-phenoxybenzoic acid
This example was made by substituting EXAMPLE 114B for EXAMPLE 1D
in EXAMPLE 1E.
Example 114D
4-(4-{[4'-chloro-4-(3-piperidin-1-ylpropoxy)-1,1'-biphenyl-2-yl]methyl}pip-
erazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)-2-phenoxybenzamide
This example was made by substituting EXAMPLE 114C for EXAMPLE 1E
in EXAMPLE 27H. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.69 (br s, 1H), 9.18 (br s, 1H), 8.63 (t, 1H), 8.46 (d,
1H), 7.75 (dd, 1H), 7.50 (m, 3H), 7.33-7.21 (m, 6H), 7.15 (d, 2H),
6.98 (m, 1H), 6.78 (m, 3H), 6.44 (d, 1H), 4.11 (t, 2H), 3.87 (dd,
2H), 3.60-3.38 (m, 10H), 3.34 (m, 4H), 3.25 (m, 4H), 2.92 (m, 2H),
2.17 (m, 2H), 1.85 (m, 3H), 1.64 (m, 6H), 1.29 (m, 2H).
Example 115
4-(4-{[4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl]methyl}pipe-
razin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}su-
lfonyl)-2-phenoxybenzamide
Example 115A
methyl
4-(4-(2-bromo-5-(2-morpholinoethoxy)benzyl)piperazin-1-yl)-2-phenox-
ybenzoate
This example was made by substituting 4-(2-chloroethyl)morpholine
hydrochloride salt for 2-chloro-N,N-dimethylethanamine
hydrochloride salt in EXAMPLE 113C.
Example 115B
methyl
4-(4-((4'-chloro-4-(2-morpholinoethoxy)biphenyl-2-yl)methyl)piperaz-
in-1-yl)-2-phenoxybenzoate
This example was made by substituting EXAMPLE 115A for EXAMPLE 68C
and 4-chlorophenylboronic acid for 4-methoxyphenylboronic acid in
EXAMPLE 68D.
Example 115C
4-(4-((4'-chloro-4-(2-morpholinoethoxy)biphenyl-2-yl)methyl)piperazin-1-yl-
)-2-phenoxybenzoic acid
This example was made by substituting EXAMPLE 115B for EXAMPLE 1D
in EXAMPLE 1E.
Example 115D
4-(4-{[4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl]methyl}pipe-
razin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}su-
lfonyl)-2-phenoxybenzamide
This example was made by substituting EXAMPLE 115C for EXAMPLE 1E
in EXAMPLE 27H. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.66 (br s, 1H), 8.63 (t, 1H), 8.46 (d, 1H), 7.75 (dd,
1H), 7.50 (m, 3H), 7.31 (m, 4H), 7.23 (m, 2H), 7.15 (m, 2H), 6.98
(m, 1H), 6.78 (m, 3H), 6.44 (d, 1H), 4.41 (m, 2H), 3.87 (m, 6H),
3.60-3.38 (m, 12H), 3.36-3.25 (m, 8H), 1.91 (m, 1H), 1.64 (m, 2H),
1.29 (m, 2H).
Example 116
4-[4-({4'-chloro-4-[3-(dimethylamino)propoxy]-1,1'-biphenyl-2-yl}methyl)pi-
perazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-
sulfonyl)-2-phenoxybenzamide
Example 116A
methyl
4-(4-(2-bromo-5-(3-(dimethylamino)propoxy)benzyl)piperazin-1-yl)-2--
phenoxybenzoate
This example was made by substituting
3-chloro-N,N-dimethylpropan-1-amine hydrochloride salt for
2-chloro-N,N-dimethylethanamine hydrochloride salt in EXAMPLE
113C.
Example 116B
methyl
4-(4-((4'-chloro-4-(3-(dimethylamino)propoxy)biphenyl-2-yl)methyl)p-
iperazin-1-yl)-2-phenoxybenzoate
This example was made by substituting EXAMPLE 116A for EXAMPLE 68C
and 4-chlorophenylboronic acid for 4-methoxyphenylboronic acid in
EXAMPLE 68D.
Example 116C
4-(4-((4'-chloro-4-(3-(dimethylamino)propoxy)biphenyl-2-yl)methyl)piperazi-
n-1-yl)-2-phenoxybenzoic acid
This example was made by substituting EXAMPLE 116B for EXAMPLE JD
in EXAMPLE 1E.
Example 116D
4-[4-({4'-chloro-4-[3-(dimethylamino)propoxy]-1,1'-biphenyl-2-yl}methyl)pi-
perazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-
sulfonyl)-2-phenoxybenzamide
This example was made by substituting EXAMPLE 116C for EXAMPLE 1E
in EXAMPLE 27H. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.64 (br s, 1H), 9.52 (br s, 1H), 8.63 (t, 1H), 8.47 (d,
1H), 7.75 (dd, 1H), 7.50 (m, 3H), 7.34 (m, 2H), 7.23 (m, 4H), 7.14
(d, 1H), 6.98 (m, 2H), 6.78 (m, 3H), 6.42 (s, 1H), 4.09 (t, 2H),
3.86 (m, 2H), 3.50-3.36 (m, 8H), 3.28 (m, 8H), 2.83 (s, 6H), 2.12
(m, 2H), 1.91 (m, 1H), 1.62 (m, 2H), 1.29 (m, 2H).
Example 117
4-(4-{[4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl]methyl}pipe-
razin-1-yl)-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(tr-
ifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
This example was made by substituting EXAMPLE 115C for EXAMPLE 27G
and EXAMPLE 163A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 8.11 (d, 1H), 7.86 (dd,
1H), 7.49 (m, 3H), 7.36-7.26 (m, 7H), 7.10 (m, 3H), 6.84 (d, 2H),
6.77 (dd, 1H), 6.41 (s, 1H), 4.38 (m, 2H), 3.84 (m, 4H), 3.55 (m,
2H), 3.50-3.30 (m, 10H), 3.28 (m, 8H), 3.20 (m, 2H), 1.86 (m, 1H),
1.55 (m, 2H), 1.26 (m, 2H).
Example 118
4-(4-{[4'-chloro-4-(3-piperidin-1-ylpropoxy)-1,1'-biphenyl-2-yl]methyl}pip-
erazin-1-yl)-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(t-
rifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
This example was made by substituting EXAMPLE 114C for EXAMPLE 27G
and EXAMPLE 163A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.65 (br s, 1H), 9.06 (br
s, 1H), 8.11 (d, 1H), 7.86 (dd, 1H), 7.49 (m, 3H), 7.36-7.20 (m,
7H), 7.06 (m, 3H), 6.83 (d, 2H), 6.76 (dd, 1H), 6.41 (s, 1H), 4.10
(t, 2H), 3.85 (dd, 2H), 3.40-3.05 (m, 16H), 2.90 (m, 2H), 2.15 (m,
2H), 1.84 (m, 3H), 1.60 (m, 6H), 1.41 (m, 2H), 1.26 (m, 2H).
Example 119
4-[4-({4'-chloro-4-[3-(dimethylamino)propoxy]-1,1'-biphenyl-2-yl}methyl)pi-
perazin-1-yl]-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(-
trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
This example was made by substituting EXAMPLE 116C for EXAMPLE 27G
and EXAMPLE 163A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 8.11 (d, 1H), 7.86 (dd,
1H), 7.49 (m, 3H), 7.36-7.26 (m, 7H), 7.06 (m, 3H), 6.84 (d, 2H),
6.76 (dd, 1H), 6.41 (d, 1H), 4.09 (t, 2H), 3.84 (dd, 2H), 3.50-3.24
(m, 14H), 3.10 (m, 2H), 2.83 (s, 6H), 2.12 (m, 2H), 1.86 (m, 1H),
1.55 (m, 2H), 1.26 (m, 2H).
Example 120
4-[4-({4'-chloro-4-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(t-
rifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
This example was made by substituting EXAMPLE 113E for EXAMPLE 27G
and EXAMPLE 163A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.75 (br s, 1H), 9.90 (br
s, 1H), 8.10 (d, 1H), 7.85 (dd, 1H), 7.49 (m, 3H), 7.38-7.25 (m,
7H), 7.11 (d, 2H), 7.03 (m, 1H), 6.82 (d, 2H), 6.77 (dd, 1H), 6.44
(s, 1H), 4.37 (t, 2H), 3.85 (m, 6H), 3.55 (m, 2H), 3.29 (m, 8H),
3.10 (m, 2H), 2.89 (s, 6H), 1.86 (m, 1H), 1.55 (m, 2H), 1.24 (m,
2H).
Example 121
4-[4-({4'-chloro-4-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl-
)-2-phenoxybenzamide
This example was made by substituting EXAMPLE 113E for EXAMPLE 27G
and EXAMPLE 68F for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.70 (br s, 1H), 9.95 (br
s, 1H), 9.73 (br s, 1H), 8.69 (t, 1H), 8.49 (d, 1H), 7.79 (dd, 1H),
7.50 (m, 3H), 7.34 (m, 2H), 7.23 (m, 3H), 7.16 (d, 1H), 7.09 (m,
1H), 7.00 (m, 1H), 6.82 (d, 2H), 6.77 (dd, 1H), 6.42 (s, 1H), 4.37
(m, 2H), 3.70 (m, 6H), 3.54 (m, 8H), 3.21 (m, 4H), 3.19 (m, 2H),
2.88 (s, 6H), 1.97 (m, 4H), 1.85 (m, 2H).
Example 122
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)-2-phenoxybenzamide
Example 122A
methyl
4-(4-(2-bromo-6-hydroxybenzyl)piperazin-1-yl)-2-phenoxybenzoate
This example was made by substituting 2-bromo-6-hydroxybenzaldehyde
for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 113A for
tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
Example 122B
methyl
4-(4-((4'-chloro-3-hydroxybiphenyl-2-yl)methyl)piperazin-1-yl)-2-ph-
enoxybenzoate
This example was made by substituting EXAMPLE 122A for EXAMPLE 68C
and 4-chlorophenylboronic acid for 4-methoxyphenylboronic acid in
EXAMPLE 68D.
Example 122C
methyl
4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-phenoxybenzoate
EXAMPLE 122B (100 mg) and 2-chloro-N,N-dimethylethanamine
hydrochloride salt (30 mg) was dissolved in mixed solvent of
dichloromethane (1.5 mL) and 50% sodium hydroxide aqueous solution
(0.5 mL), followed by addition of tetrabutylammonium iodide (15
mg). The reaction mixture was stirred at room temperature
overnight. The reaction mixture was diluted with ethyl acetate, and
washed with water and brine. The organic phase was dried over
Na.sub.2SO.sub.4 and concentrated. Flash column purification was
performed with 0-5% methanol/dichloromethane to afford the
product.
Example 122D
4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin
1-yl)-2-phenoxybenzoic acid
This example was made by substituting EXAMPLE 122C for EXAMPLE 1D
in EXAMPLE 1E.
Example 122E
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)-2-phenoxybenzamide
This example was made by substituting EXAMPLE 122D for EXAMPLE 1E
in EXAMPLE 27H. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 10.20 (br s, 1H), 9.46 (br s, 1H), 8.65 (t, 1H), 8.47 (d,
1H), 7.78 (d, 1H), 7.75 (dd, 1H), 7.52 (m, 4H), 7.38 (m, 3H), 7.23
(m, 3H), 7.12 (m, 1H), 6.98 (m, 2H), 6.78 (d, 2H), 6.76 (dd, 1H),
6.43 (s, 1H), 4.43 (m, 2H), 3.87 (m, 2H), 3.62 (m, 4H), 3.35-3.15
(m, 12H), 2.90 (s, 6H), 1.90 (m, 1H), 1.62 (m, 2H), 1.27 (m,
2H).
Example 123
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl-
)-2-phenoxybenzamide
This example was made by substituting EXAMPLE 122C for EXAMPLE 1E
and EXAMPLE 68F for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 10.01 (brs, 1H), 9.63 (brs, 1H),
9.32 (brs, 1H), 8.69 (t, 1H), 8.49 (d, 1H), 7.80 (dd, 1H), 7.52 (m,
4H), 7.38 (m, 2H), 7.25 (m, 3H), 7.15 (d, 1H), 7.01 (m, 1H), 6.95
(m, 1H), 6.81 (d, 2H), 6.76 (m, 1H), 6.41 (s, 1H), 4.43 (m, 4H),
3.56-3.51 (m, 8H), 3.20 (m, 4H), 3.10 (m, 6H), 2.91 (s, 6H), 1.98
(m, 4H), 1.85 (m, 2H).
Example 124
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(t-
rifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
This example was made by substituting EXAMPLE 122C for EXAMPLE 27G
and EXAMPLE 163A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.71 (br s, 1H), 9.89 (br
s, 1H), 9.14 (br s, 1H), 8.11 (d, 1H), 7.86 (dd, 1H), 7.52 (m, 4H),
7.38 (m, 2H), 7.29 (m, 3H), 7.20 (m, 1H), 7.11 (d, 1H), 7.05 (m,
1H), 6.95 (m, 1H), 6.83 (d, 2H), 6.76 (dd, 1H), 6.40 (s, 1H), 4.41
(m, 2H), 3.85 (m, 2H), 3.59 (m, 4H), 3.44 (m, 2H), 3.28 (m, 8H),
3.06 (m, 2H), 2.91 (s, 6H), 1.84 (m, 1H), 1.55 (m, 2H), 1.26 (m,
2H).
Example 125
4-[4-({4'-chloro-4-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-yl-
methyl)amino]phenyl}sulfonyl)benzamide
Example 125A
4'-chloro-4-hydroxybiphenyl-2-carbaldehyde
This example was made by substituting 2-bromo-5-hydroxybenzaldehyde
for EXAMPLE 68C and 4-chlorophenylboronic acid for
4-methoxyphenylboronic acid in EXAMPLE 68D.
Example 125B
4'-chloro-4-(2-(dimethylamino)ethoxy)biphenyl-2-carbaldehyde
This example was made by substituting EXAMPLE 125A for EXAMPLE 122B
in EXAMPLE 122C.
Example 125C
methyl
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)bi-
phenyl-2-yl)methyl)piperazin-1-yl)benzoate
This example was made by substituting EXAMPLE 125B for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 125D
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)biphenyl--
2-yl)methyl)piperazin-1-yl)benzoic acid
This example was made by substituting EXAMPLE 125C for EXAMPLE 1D
in EXAMPLE 1E.
Example 125E
4-[4-({4'-chloro-4-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-yl-
methyl)amino]phenyl}sulfonyl)benzamide
This example was made by substituting EXAMPLE 125D for EXAMPLE 1E
in EXAMPLE 27H. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.46 (br s, 1H), 11.25 (s, 1H), 9.80 (br s, 1H), 8.60 (t,
1H), 8.48 (d, 1H), 7.65 (dd, 1H), 7.55 (d, 1H), 7.46 (d, 2H), 7.28
(m, 5H), 7.15 (d, 1H), 7.10 (m, 1H), 7.04 (d, 1H), 6.94 (m, 1H),
6.73 (dd, 1H), 6.36 (m, 2H), 6.26 (m, 1H), 4.35 (t, 2H), 3.85 (m,
6H), 3.54 (m, 4H), 3.31 (m, 6H), 3.06 (m, 2H), 2.88 (s, 6H), 1.88
(m, 1H), 1.60 (m, 2H), 1.28 (m, 2H).
Example 126
4-[4-({4'-chloro-4-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-yl-
methyl)amino]phenyl}sulfonyl)benzamide
Example 126A
methyl
2-(1H-indol-5-yloxy)-4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)bi-
phenyl-2-yl)methyl)piperazin-1-yl)benzoate
This example was made by substituting EXAMPLE 125B for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 150A for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 126B
2-(1H-indol-5-yloxy)-4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)biphenyl--
2-yl)methyl)piperazin-1-yl)benzoic acid
This example was made by substituting EXAMPLE 126A for EXAMPLE 1D
in EXAMPLE 1E.
Example 126C
4-[4-({4'-chloro-4-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-yl-
methyl)amino]phenyl}sulfonyl)benzamide
This example was made by substituting EXAMPLE 126B for EXAMPLE 1E
in EXAMPLE 27H. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.35 (br s, 1H), 11.17 (s, 1H), 9.85 (br s, 1H), 8.61 (t,
1H) 8.57 (d, 1H), 7.77 (dd, 1H), 7.54 (d, 1H), 7.46 (d, 2H), 7.38
(m, 2H), 7.30 (m, 4H), 7.09 (m, 3H), 6.84 (dd, 1H), 6.69 (dd, 1H),
6.36 (m, 1H), 6.26 (m, 1H), 4.35 (t, 2H), 3.85 (m, 6H), 3.54 (m,
4H), 3.31 (m, 6H), 3.06 (m, 2H), 2.88 (s, 6H), 1.88 (m, 1H), 1.60
(m, 2H), 1.28 (m, 2H).
Example 127
4-(4-{[4'-chloro-1,1'-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-y-
loxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)benzamide
Example 127A
4'-chloro-4-(2-morpholinoethoxy)biphenyl-2-carbaldehyde
This example was made by substituting EXAMPLE 125A for EXAMPLE 122B
in and 4-(2-chloroethyl)morpholine hydrochloride salt for
2-chloro-N,N-dimethylethanamine hydrochloride salt EXAMPLE
122C.
Example 127B
methyl
2-(1H-indol-5-yloxy)-4-(4-((4'-chloro-4-(2-morpholinoethoxy)bipheny-
l-2-yl)methyl)piperazin-1-yl)benzoate
This example was made by substituting EXAMPLE 127A for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 150A for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 127C
2-(1H-indol-5-yloxy)-4-(4-((4'-chloro-4-(2-morpholinoethoxy)biphenyl-2-yl)-
methyl)piperazin-1-yl)benzoic acid
This example was made by substituting EXAMPLE 127B for EXAMPLE 1D
in EXAMPLE 1E.
Example 127D
4-(4-{[4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylm-
ethyl)amino]phenyl}sulfonyl)benzamide
This example was made by substituting EXAMPLE 127C for EXAMPLE 1E
in EXAMPLE 27H. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.35 (br s, 1H), 11.17 (s, 1H), 8.61 (t, 1H), 8.57 (d,
1H), 7.77 (dd, 1H), 7.54 (d, 1H), 7.46 (d, 2H), 7.38 (m, 2H), 7.29
(m, 4H), 7.09 (m, 3H), 6.84 (dd, 1H), 6.69 (dd, 1H), 6.36 (m, 1H),
6.26 (d, 1H), 4.39 (t, 2H), 3.85 (m, 6H), 3.54 (m, 10H), 3.31 (m,
8H), 3.06 (m, 2H), 1.88 (m, 1H), 1.60 (m, 2H), 1.27 (m, 2H).
Example 128
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-yl-
methyl)amino]phenyl}sulfonyl)benzamide
Example 128A
4'-chloro-3-hydroxybiphenyl-2-carb aldehyde
This example was made by substituting 2-bromo-6-hydroxybenzaldehyde
for EXAMPLE 68C and 4-chlorophenylboronic acid for
4-methoxyphenylboronic acid in EXAMPLE 68D.
Example 128B
4'-chloro-3-(2-(dimethylamino)ethoxy)biphenyl-2-carbaldehyde
This example was made by substituting EXAMPLE 128A for EXAMPLE 122B
in EXAMPLE 122C.
Example 128C
methyl
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)bi-
phenyl-2-yl)methyl)piperazin-1-yl)benzoate
This example was made by substituting EXAMPLE 128B for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 128D
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)biphenyl--
2-yl)methyl)piperazin-1-yl)benzoic acid
This example was made by substituting EXAMPLE 128C for EXAMPLE 1D
in EXAMPLE 1E.
Example 128E
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-yl-
methyl)amino]phenyl}sulfonyl)benzamide
This example was made by substituting EXAMPLE 128D for EXAMPLE 1E
in EXAMPLE 27H. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.15 (s, 1H), 8.47 (t, 1H) 8.45 (d, 1H), 7.68 (dd, 1H),
7.57 (d, 1H), 7.50 (d, 2H), 7.42 (d, 2H), 7.32 (m, 1H), 7.24 (m,
1H), 7.12 (d, 1H), 7.05 (d, 1H), 6.94 (m, 2H), 6.84 (d, 1H), 6.66
(dd, 1H), 6.35 (d, 1H), 6.25 (m, 2H), 4.17 (t, 2H), 3.85 (m, 2H),
3.54 (m, 10H), 3.40 (m, 6H), 3.30 (s, 6H), 3.02 (m, 2H), 2.96 (m,
4H), 2.28 (m, 4H), 1.88 (m, 1H), 1.60 (m, 2H), 1.28 (m, 2H).
Example 129
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-yl-
methyl)amino]phenyl}sulfonyl)benzamide
Example 129A
methyl
2-(1H-indol-5-yloxy)-4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)bi-
phenyl-2-yl)methyl)piperazin-1-yl)benzoate
This example was made by substituting EXAMPLE 128B for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 150A for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 129B
2-(1H-indol-5-yloxy)-4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)biphenyl--
2-yl)methyl)piperazin-1-yl)benzoic acid
This example was made by substituting EXAMPLE 129A for EXAMPLE 1D
in EXAMPLE 1E.
Example 129C
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-yl-
methyl)amino]phenyl}sulfonyl)benzamide
This example was made by substituting EXAMPLE 129B for EXAMPLE 1E
in EXAMPLE 27H. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.38 (br s, 1H), 11.19 (s, 1H), 10.00 (br s, 1H), 8.61 (t,
1H) 8.58 (d, 1H), 7.79 (dd, 1H), 7.53 (m, 4H), 7.39 (m, 4H), 7.19
(m, 1H), 7.11 (m, 2H), 6.93 (d, 1H), 6.84 (dd, 1H), 6.69 (dd, 1H),
6.39 (m, 1H), 6.19 (d, 1H), 4.40 (m, 2H), 3.85 (m, 8H), 3.58 (m,
2H), 3.27 (m, 6H), 3.06 (m, 2H), 2.89 (s, 6H), 1.89 (m, 1H), 1.60
(m, 2H), 1.27 (m, 2H).
Example 130
4-(4-{[4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylm-
ethyl)amino]phenyl}sulfonyl)benzamide
Example 130A
methyl
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-4-(2-morpholinoethoxy)bipheny-
l-2-yl)methyl)piperazin-1-yl)benzoate
This example was made by substituting EXAMPLE 127A for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 130B
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-4-(2-morpholinoethoxy)biphenyl-2-yl)-
methyl)piperazin-1-yl)benzoic acid
This example was made by substituting EXAMPLE 130A for EXAMPLE 1D
in EXAMPLE 1E.
Example 130C
4-(4-{[4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylm-
ethyl)amino]phenyl}sulfonyl)benzamide
This example was made by substituting EXAMPLE 130B for EXAMPLE 1E
in EXAMPLE 27H. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.47 (br s, 1H), 11.23 (s, 1H), 8.59 (t, 1H) 8.47 (d, 1H),
7.63 (dd, 1H), 7.54 (d, 1H), 7.47 (d, 2H), 7.27 (m, 6H), 7.13 (m,
2H), 7.03 (m, 1H), 6.93 (m, 1H), 6.74 (dd, 1H), 6.35 (m, 1H), 6.24
(m, 1H), 4.39 (t, 2H), 3.85 (m, 6H), 3.54 (m, 10H), 3.26 (m, 10H),
1.88 (m, 1H), 1.59 (m, 2H), 1.27 (m, 2H).
Example 131
4-(4-{[4'-chloro-3-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-4-yloxy)-N-(({3-nitro-4-[(tetrahydro-2H-pyran-4-yl-
methyl)amino]phenyl}sulfonyl)benzamide
Example 131A
4'-chloro-3-(2-morpholinoethoxy)biphenyl-2-carbaldehyde
This example was made by substituting EXAMPLE 128A for EXAMPLE 122B
and 4-(2-chloroethyl)morpholine hydrochloride salt for
2-chloro-N,N-dimethylethanamine hydrochloride salt in EXAMPLE
122C.
Example 131B
methyl
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-3-(2-morpholinoethoxy)bipheny-
l-2-yl)methyl)piperazin-1-yl)benzoate
This example was made by substituting EXAMPLE 131A for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 131C
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-3-(2-morpholinoethoxy)biphenyl-2-yl)-
methyl)piperazin-1-yl)benzoic acid
This example was made by substituting EXAMPLE 131B for EXAMPLE 1D
in EXAMPLE 1E.
Example 131D
4-(4-{[4'-chloro-3-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylm-
ethyl)amino]phenyl}sulfonyl)benzamide
This example was made by substituting EXAMPLE 131C for EXAMPLE 1E
in EXAMPLE 27H. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.49 (br s, 1H), 11.25 (s, 1H), 8.59 (t, 1H), 8.50 (d,
1H), 7.68 (dd, 1H), 7.52 (m, 4H), 7.34 (d, 2H), 7.28 (m, 1H), 7.18
(m, 2H), 7.06 (d, 1H), 6.94 (m, 2H), 6.73 (dd, 1H), 6.40 (d, 1H),
6.33 (d, 1H), 6.24 (m, 1H), 4.43 (t, 2H), 3.85 (m, 10H), 3.61 (m,
6H), 3.27 (m, 8H), 3.02 (m, 2H), 1.88 (m, 1H), 1.60 (m, 2H), 1.28
(m, 2H).
Example 132
4-(4-{[4'-chloro-3-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylm-
ethyl)amino]phenyl}sulfonyl)benzamide
Example 132A
methyl
2-(1H-indol-5-yloxy)-4-(4-((4'-chloro-3-(2-morpholinoethoxy)bipheny-
l-2-yl)methyl)piperazin-1-yl)benzoate
This example was made by substituting EXAMPLE 131A for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 150A for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 132B
2-(1H-indol-5-yloxy)-4-(4-((4'-chloro-3-(2-morpholinoethoxy)biphenyl-2-yl)-
methyl)piperazin-1-yl)benzoic acid
This example was made by substituting EXAMPLE 132A for EXAMPLE 1D
in EXAMPLE 1E.
Example 132C
4-(4-{[4'-chloro-3-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylm-
ethyl)amino]phenyl}sulfonyl)benzamide
This example was made by substituting EXAMPLE 132B for EXAMPLE 1E
in EXAMPLE 27H. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.34 (br s, 1H), 11.17 (s, 1H), 8.60 (t, 1H), 8.58 (d,
1H), 7.79 (dd, 1H), 7.50 (m, 4H), 7.39 (m, 4H), 7.19 (d, 1H), 7.14
(d, 1H), 7.09 (d, 1H), 6.93 (d, 1H), 6.84 (dd, 1H), 6.69 (dd, 1H),
6.39 (m, 1H), 6.19 (d, 1H), 4.40 (m, 2H), 3.85 (m, 6H), 3.48 (m,
8H), 3.27 (m, 10H), 3.06 (m, 2H), 1.89 (m, 1H), 1.60 (m, 2H), 1.27
(m, 2H).
Example 133
4-[4-({4'-chloro-4-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-
-2-phenoxybenzamide
This example was made by substituting EXAMPLE 113D for EXAMPLE 27G
and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 8.34 (d, 1H), 8.05 (d, 1H),
7.69 (dd, 1H), 7.59 (d, 1H), 7.42 (m, 4H), 7.14 (m, 3H), 7.09 (d,
1H), 6.98 (d, 1H), 6.92 (dd, 1H), 6.87 (m, 1H), 6.84 (m, 3H), 6.30
(d, 1H), 4.16 (t, 2H), 3.07 (m, 6H), 2.95 (m, 4H), 2.56 (m, 2H),
2.45 (s, 3H), 2.35 (m, 4H), 2.03 (m, 2H), 1.68 (m, 2H).
Example 134
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)-
amino]phenyl}sulfonyl)benzamide
This example was made by substituting EXAMPLE 129B for EXAMPLE 27G
and EXAMPLE 68F for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.34 (br s, 1H), 11.17 (s,
1H), 9.65 (br s, 1H), 8.63 (t, 1H), 8.60 (d, 1H), 7.86 (dd, 1H),
7.53 (d, 2H), 7.41 (m, 6H), 7.15 (m, 3H), 6.92 (m, 1H), 6.84 (dd,
1H), 6.66 (dd, 1H), 6.38 (m, 1H), 6.16 (d, 1H), 4.37 (m, 2H), 3.50
(m, 12H), 3.17 (m, 4H), 2.97 (m, 4H), 2.88 (s, 6H), 1.95 (m, 4H),
1.85 (m, 2H).
Example 135
4-[4-({4'-chloro-4-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)-
amino]phenyl}sulfonyl)benzamide
This example was made by substituting EXAMPLE 126B for EXAMPLE 27G
and EXAMPLE 68F for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.29 (br s, 1H), 11.16 (s,
1H), 9.56 (br s, 1H), 8.63 (t, 1H), 8.60 (d, 1H), 7.85 (dd, 1H),
7.53 (d, 1H), 7.41 (m, 4H), 7.32 (m, 3H), 7.24 (m, 1H), 7.12 (m,
3H), 6.84 (dd, 1H), 6.66 (dd, 1H), 6.38 (m, 1H), 6.18 (d, 1H), 4.33
(t, 2H), 3.50 (m, 12H), 3.17 (m, 4H), 2.97 (m, 4H), 2.86 (s, 6H),
1.95 (m, 4H), 1.85 (m, 2H).
Example 136
4-(4-{[4'-chloro-4-(2-morpholin-4-ylethoxy)-1,1'-biphenyl-2-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)a-
mino]phenyl}sulfonyl)benzamide
This example was made by substituting EXAMPLE 127C for EXAMPLE 27G
and EXAMPLE 68F for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.29 (br s, 1H), 11.16 (s,
1H), 9.54 (br s, 1H), 8.63 (t, 1H), 8.60 (d, 1H), 7.85 (dd, 1H),
7.53 (d, 1H), 7.45 (d, 2H), 7.38 (m, 2H), 7.31 (d, 2H), 7.23 (m,
2H), 7.12 (m, 3H), 6.84 (dd, 1H), 6.66 (dd, 1H), 6.38 (m, 1H), 6.18
(d, 1H), 4.36 (t, 2H), 3.82 (m, 4H), 3.50 (m, 8H), 3.17 (m, 10H),
2.98 (m, 4H), 1.95 (m, 6H), 1.85 (m, 2H).
Example 137
4-[4-({4'-chloro-4-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-N-[(3-nitro-4-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]amino}-
phenyl)sulfonyl]-2-phenoxybenzamide
This example was made by substituting EXAMPLE 113E for EXAMPLE 27G
and EXAMPLE 108A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.71 (br s, 1H), 9.81 (br
s, 1H), 8.46 (d, 1H), 8.29 (d, 1H), 7.75 (dd, 1H), 7.50 (m, 3H),
7.30 (m, 4H), 7.21 (m, 3H), 7.10 (m, 1H), 6.97 (m, 1H), 6.77 (m,
3H), 6.43 (s, 1H), 4.36 (t, 2H), 3.72 (m, 2H), 3.58 (m, 4H), 3.23
(m, 6H), 2.95 (m, 4H), 2.89 (s, 6H), 2.60 (m, 2H), 1.92 (m, 2H),
1.68 (m, 2H).
Example 138
4-(4-{[4'-chloro-4-(2-pyrrolidin-1-ylethoxy)-1,1'-biphenyl-2-yl]methyl}pip-
erazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)-2-phenoxybenzamide
Example 138A
methyl
4-(4-((4'-chloro-4-hydroxybiphenyl-2-yl)methyl)piperazin-1-yl)-2-ph-
enoxybenzoate
This example was made by substituting EXAMPLE 113B for EXAMPLE 68C
and 4-chlorophenylboronic acid for 4-methoxyphenylboronic acid in
EXAMPLE 68D.
Example 138B
methyl
4-(4-((4'-chloro-4-(2-(pyrrolidin-1-yl)ethoxy)biphenyl-2-yl)methyl)-
piperazin-1-yl)-2-phenoxybenzoate
This example was made by substituting EXAMPLE 138A for EXAMPLE 113B
and 1-(2-chloroethyl)pyrrolidine HCl salt for
2-chloro-N,N-dimethylethanamine hydrochloride salt in EXAMPLE
113C.
Example 138C
4-(4-((4'-chloro-4-(2-(pyrrolidin-1-yl)ethoxy)biphenyl-2-yl)methyl)piperaz-
in-1-yl)-2-phenoxybenzoic acid
This example was made by substituting EXAMPLE 138B for EXAMPLE 1D
in EXAMPLE 1E.
Example 138D
4-(4-{[4'-chloro-4-(2-pyrrolidin-1-ylethoxy)-1,1'-biphenyl-2-yl]methyl}pip-
erazin-1-yl)-N-(3-nitro-4-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)-2-phenoxybenzamide
This example was made by substituting EXAMPLE 138C for EXAMPLE 1E
in EXAMPLE 27H. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.64 (br s, 1H), 9.98 (br s, 1H), 8.62 (d, 1H), 8.47 (d,
1H), 7.75 (dd, 1H), 7.50 (m, 3H), 7.26 (m, 6H), 7.14 (m, 2H), 6.99
(m, 1H), 6.81 (d, 2H), 6.77 (dd, 1H), 6.43 (d, 1H), 4.36 (t, 2H),
3.86 (dd, 2H), 3.62 (m, 8H), 3.28 (m, 8H), 3.10 (m, 4H), 2.04 (m,
2H), 1.90 (m, 3H), 1.65 (m, 2H), 1.29 (m, 2H).
Example 139
4-[4-({4'-chloro-4-[2-(diisopropylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)-
piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pheny-
l}sulfonyl)-2-phenoxybenzamide
Example 139A
methyl
4-(4-((4'-chloro-4-(2-(diisopropylamino)ethoxy)biphenyl-2-yl)methyl-
)piperazin-1-yl)-2-phenoxybenzoate
This example was made by substituting EXAMPLE 138A for EXAMPLE 113B
and 2-diisopropylaminoethyl chloride hydrochloride salt for
2-chloro-N,N-dimethylethanamine hydrochloride salt in EXAMPLE
113C.
Example 139B
4-(4-((4'-chloro-4-(2-(diisopropylamino)ethoxy)biphenyl-2-yl)methyl)pipera-
zin-1-yl)-2-phenoxybenzoic acid
This example was made by substituting EXAMPLE 139A for EXAMPLE 1D
in EXAMPLE 1E.
Example 139C
4-[4-({4'-chloro-4-[2-(diisopropylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)-
piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pheny-
l}sulfonyl)-2-phenoxybenzamide
This example was made by substituting EXAMPLE 139B for EXAMPLE 1E
in EXAMPLE 27H. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.65 (br s, 1H), 8.75 (br s, 1H), 8.62 (d, 1H), 8.47 (d,
1H), 7.75 (dd, 1H), 7.50 (m, 3H), 7.31 (m, 4H), 7.23 (m, 2H), 7.13
(m, 2H), 6.99 (m, 1H), 6.79 (m, 3H), 6.44 (m, 1H), 4.31 (t, 2H),
3.86 (dd, 2H), 3.62 (m, 10H), 3.28 (m, 6H), 1.91 (m, 1H), 1.62 (m,
2H), 1.32 (m, 14H).
Example 140
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(2,3-dihydro--
1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phe-
nyl}sulfonyl)benzamide
A suspension of EXAMPLE 40D (22.57 mg) and sodium cyanoborohydride
(25 mg) in acetic acid (5 ml) was stirred at room temperature for 2
hours. The product was partitioned between dichloromethane and
water. The organic layer was separated, dried over
Na.sub.2SO.sub.4, and concentrated. The crude product was purified
by RP HPLC (C8, 30-100 acetonitrile/water/0.1% trifluoroacetic
acid). .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.56 (s, 1H), 9.60 (s, 1H), 8.66 (t, 1H), 8.57 (d, 1H), 7.85 (dd,
1H), 7.71 (s, 1H), 7.46-7.60 (m, 5H), 7.29-7.42 (m, 3H), 7.25 (d,
1H), 6.95 (s, 1H), 6.82 (s, 1H), 6.73 (d, 1H), 6.36 (s, 1H), 4.32
(bs, 2H), 3.85 (dd, 4H), 3.59 (t, 4H), 3.35 (t, 2H), 3.27 (t, 2H),
3.02 (t, 4H), 1.80-1.99 (m, 1H), 1.62 (d, 2H), 1.15-1.36 (m,
2H).
Example 141
4-(4-{[2-(4-chlorophenyl)cyclohept-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H--
indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfon-
yl)benzamide
Example 141A
(Z)-methyl
2-(trifluoromethylsulfonyloxy)cyclohept-1-enecarboxylate
This example was prepared by substituting methyl
2-oxocycloheptanecarboxylate for
5,5-dimethyl-2-methoxycarbonylcyclohexanone in EXAMPLE 18A.
Example 141B
(Z)-methyl 2-(4-chlorophenyl)cyclohept-1-enecarboxylate
This example was prepared by substituting EXAMPLE 141A for EXAMPLE
18A in EXAMPLE 18B.
Example 141C
(Z)-(2-(4-chlorophenyl)cyclohept-1-enyl)methanol
This example was prepared by substituting EXAMPLE 141B for EXAMPLE
18B in EXAMPLE 18C.
Example 141D
(Z)-2-(4-chlorophenyl)cyclohept-1-enecarbaldehyde
This example was prepared by substituting EXAMPLE 141C for EXAMPLE
143C in EXAMPLE 143D.
Example 141E
(Z)-ethyl
2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-enyl)m-
ethyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 141D for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 141F
(Z)-2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-enyl)methyl)-
piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 141E for EXAMPLE
143E in EXAMPLE 143F.
Example 141G
4-(4-{[2-(4-chlorophenyl)cyclohept-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H--
indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfon-
yl)benzamide
This example was prepared by substituting EXAMPLE 141F for EXAMPLE
1E and EXAMPLE 68F for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.45 (m, 1H), 10.03 (m,
1H), 8.58 (m, 2H), 8.30 (m, 1H), 7.26 (m, 11H), 6.25 (m, 2H), 3.14
(m, 12H), 2.73 (m, 5H), 1.94 (m, 12H), 1.54 (m, 5H).
Example 142
4-(4-{[2-(4-chlorophenyl)cyclooct-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-i-
ndol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfony-
l)benzamide
Example 142A
(Z)-ethyl
2-(trifluoromethylsulfonyloxy)cyclooct-1-enecarboxylate
This example was prepared by substituting ethyl
2-oxocyclooctanecarboxylate for
5,5-dimethyl-2-methoxycarbonylcyclohexanone in EXAMPLE 18A.
Example 142B
(Z)-ethyl 2-(4-chlorophenyl)cyclooct-1-enecarboxylate
This example was prepared by substituting EXAMPLE 142A for EXAMPLE
18A in EXAMPLE 18B.
Example 142C
(Z)-(2-(4-chlorophenyl)cyclooct-1-enyl)methanol
This example was prepared by substituting EXAMPLE 142B for EXAMPLE
18B in EXAMPLE 18C.
Example 142D
(Z)-2-(4-chlorophenyl)cyclooct-1-enecarbaldehyde
This example was prepared by substituting EXAMPLE 142C for EXAMPLE
143C in EXAMPLE 143D.
Example 142E
(Z)-ethyl
2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)cyclooct-1-enyl)me-
thyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 142D for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 142F
(Z)-2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)cyclooct-1-enyl)methyl)p-
iperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 142E for EXAMPLE
143E in EXAMPLE 143F.
Example 142G
4-(4-{[2-(4-chlorophenyl)cyclooct-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-i-
ndol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfony-
l)benzamide
This example was prepared by substituting EXAMPLE 142F for EXAMPLE
1E and EXAMPLE 68F for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d6) .delta. 11.51 (m, 1H), 10.01 (m, 1H),
8.58 (m, 2H), 7.26 (m, 12H), 6.35 (m, 2H), 3.14 (m, 13H), 2.73 (m,
5H), 1.88 (m, 7H), 1.45 (m, 10H).
Example 143
4-(4-{[2-(4-chlorophenyl)cyclopent-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H--
indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfon-
yl)benzamide
Example 143A
ethyl 2-(trifluoromethylsulfonyloxy)cyclopent-1-enecarboxylate
This example was prepared by substituting ethyl
2-oxocyclopentanecarboxylate for
5,5-dimethyl-2-methoxycarbonylcyclohexanone in EXAMPLE 18A.
Example 143B
ethyl 2-(4-chlorophenyl)cyclopent-1-enecarboxylate
This example was prepared by substituting EXAMPLE 143A for EXAMPLE
18A in EXAMPLE 18B.
Example 143C
(2-(4-chlorophenyl)cyclopent-1-enyl)methanol
This example was prepared by substituting EXAMPLE 143B for EXAMPLE
18B in EXAMPLE 18C.
Example 143D
2-(4-chlorophenyl)cyclopent-1-enecarbaldehyde
To a solution of oxalyl chloride (1.1 g) in dichloromethane (30 ml)
at -78.degree. C. was added dimethylsulfoxide (6.12 ml). The
mixture was stirred at -78.degree. C. for 30 minutes, and then a
solution of EXAMPLE 143C (1.2 g) in dichloromethane (10 ml) was
added. The mixture was stirred at -78.degree. C. for 2 hours before
the addition of triethylamine (10 ml). The mixture was stirred
overnight and the temperature was allowed to rise to room
temperature.
The mixture was diluted with ether (300 ml) and washed with water,
brine and dried over Na.sub.2SO.sub.4. Evaporation of solvent and
column purification (5% ethyl acetate in hexane) to give the
product.
Example 143E
ethyl
2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)cyclopent-1-enyl)methy-
l)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 143D for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 143F
2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)cyclopent-1-enyl)methyl)pipe-
razin-1-yl)benzoic acid
To a solution of EXAMPLE 143E (254 mg) in tetrahydrofuran (4 ml),
methanol (2 ml) and water (2 ml) was added LiOH--H.sub.2O (126 mg).
The mixture was stirred overnight. The mixture was then neutralized
with 5% HCl and diluted with ethyl acetate (200 ml). After washing
with brine, it was dried over Na.sub.2SO.sub.4. Evaporation of
solvent gave the product.
Example 143G
4-(4-{[2-(4-chlorophenyl)cyclopent-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H--
indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfon-
yl)benzamide
This example was prepared by substituting EXAMPLE 143F for EXAMPLE
1E and EXAMPLE 68F for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d6) .delta. ppm 11.41 (m, 1H), 10.19 (m,
1H), 8.58 (m, 2H), 7.26 (m, 14H), 6.33 (m, 2H), 3.80 (m, 4H), 3.13
(m, 12H), 2.69 (m, 5H), 1.95 (m, 7H).
Example 144
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrop-
henyl}sulfonyl)benzamide
Example 144A
methyl 4,4-dimethyl-2-oxocyclopentanecarboxylate
This compound was prepared according to WO 2006/035061 (page
53).
Example 144B
methyl
4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclopent-1-enecarboxyla-
te
This example was prepared by substituting ethyl
2-oxocyclopentanecarboxylate for
5,5-dimethyl-2-methoxycarbonylcyclohexanone in EXAMPLE 18A.
Example 144C
ethyl 2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-enecarboxylate
This example was prepared by substituting EXAMPLE 144B for EXAMPLE
18A in EXAMPLE 18B.
Example 144D
(2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-enyl)methanol
This example was prepared by substituting EXAMPLE 144C for EXAMPLE
18B in EXAMPLE 18C.
Example 144E
2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-enecarbaldehyde
This example was prepared by substituting EXAMPLE 144D for EXAMPLE
143C in EXAMPLE 143D.
Example 144F
ethyl
2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-
-1-enyl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 144E for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 144G
2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-eny-
l)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 144F for EXAMPLE
143E in EXAMPLE 143F.
Example 144H
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrop-
henyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 144G for EXAMPLE
1E and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d6) .delta. 11.59 (m, 1H), 11.25 (s, 1H),
9.53 (m, 1H), 8.50 (d, 1H), 8.16 (d, 1H), 8.16 (d, 1H), 7.80 (m,
1H), 7.56 (d, 1H), 7.26 (m, 7H), 6.95 (m, 1H), 6.77 (dd, 1H), 6.41
(m, 2H), 6.23 (s, 1H), 2.87 (m, 10H), 2.28 (m, 12H), 1.11 (m,
6H).
Example 145
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide
Example 145A
methyl 6,6-dimethyl-4-oxotetrahydro-2H-pyran-3-carboxylate
To a suspension of hexane-washed NaH (0.72 g, 60%) in
tetrahydrofuran (30 ml) was added a solution of
2,2-dimethyldihydro-2H-pyran-4(3H)-one (2.0 g) in tetrahydrofuran
(20 ml). The suspension was stirred for 30 minutes. The
dimethylcarbonate (6.31 ml) was added dropwise by syringe. The
mixture was heated to reflux for 4 hours. The mixture was acidified
with 5% HCl and extracted with dichloromethane (3.times.100 ml) and
washed with water, brine and dried over Na.sub.2SO.sub.4. After
evaporation, the crude product was loaded on a column and eluted
with 10% ethyl acetate in hexane to give the product.
Example 145B
methyl
6,6-dimethyl-4-(trifluoromethylsulfonyloxy)-5,6-dihydro-2H-pyran-3--
carboxylate
This example was prepared by substituting EXAMPLE 145A for
5,5-dimethyl-2-methoxycarbonylcyclohexanone in EXAMPLE 18A.
Example 145C
methyl
4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-carboxylate
This example was prepared by substituting EXAMPLE 145B for EXAMPLE
18A in EXAMPLE 18B.
Example 145D
(4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methanol
This example was prepared by substituting EXAMPLE 145C for EXAMPLE
18B in EXAMPLE 18C.
Example 145E
4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-carbaldehyde
This example was prepared by substituting EXAMPLE 145D for EXAMPLE
143C in EXAMPLE 143D.
Example 145F
ethyl
2-(1H-indol-4-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihy-
dro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 145E for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 145G
2-(1H-indol-4-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-
-pyran-3-yl)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 145F for EXAMPLE
143E in EXAMPLE 143F.
Example 145H
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 145G for EXAMPLE
1E and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d6) .delta. 11.56 (m, 1H), 11.26 (s, 1H),
9.52 (m, 1H), 8.51 (m, 1H), 8.16 (d, 1H), 7.80 (dd, 1H), 7.55 (d,
1H), 7.41 (d, 2H), 7.28 (t, 1H), 7.17 (m, 4H), 6.96 (m, 2H), 6.74
(d, 1H), 6.39 (m, 2H), 6.23 (s, 1H), 4.18 (s, 2H), 3.85 (m, 3H),
2.93 (m, 10H), 2.10 (m, 7H), 1.22 (s, 6H).
Example 146
4-(4-{[2-(4-chlorophenyl)cyclooct-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-i-
ndol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl-
)benzamide
This example was prepared by substituting EXAMPLE 142F for EXAMPLE
1E and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d6) 611.59 (s, 1H), 11.25 (s, 1H), 9.36 (m,
2H), 8.50 (d, 1H), 8.16 (d, 1H), 7.79 (dd, 1H), 7.55 (d, 1H), 7.40
(d, 2H), 7.28 (m, 1H), 7.14 (m, 5H), 6.96 (t, 1H), 6.74 (dd, 1H),
6.38 (m, 2H), 6.23 (s, 1H), 2.91 (m, 14H), 2.27 (m, 6H), 1.49 (m,
11H).
Example 147
4-(4-{[2-(4-chlorophenyl)cyclohept-1-en-1-yl]methyl}piperazin-1-yl)-2-(11H-
-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfon-
yl)benzamide
This example was prepared by substituting EXAMPLE 141F for EXAMPLE
1E and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d6) .delta. 11.60 (s, 1H), 11.26 (s, 1H),
9.32 (m, 2H), 8.51 (m, 1H), 8.16 (d, 1H), 7.79 (m, 1H), 7.55 (d,
1H), 7.39 (d, 2H), 7.29 (t, 1H), 7.14 (m, 4H), 6.97 (t, 1H), 6.75
(dd, 1H), 6.40 (m, 2H), 6.22 (s, 1H), 2.94 (m, 17H), 2.27 (m, 4H),
1.80 (m, 4H), 1.55 (m, 5H).
Example 148
4-(4-{[2-(4-chlorophenyl)cyclopent-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H--
indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfony-
l)benzamide
This example was prepared by substituting EXAMPLE 143F for EXAMPLE
1E and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d6) .delta. 11.60 (s, 1H), 11.26 (s, 1H),
9.47 (m, 2H), 8.51 (m, 1H), 8.16 (d, 1H), 7.77 (m, 1H), 7.56 (d,
1H), 7.43 (d, 2H), 7.20 (m, 6H), 6.96 (t, 1H), 6.77 (dd, 1H), 6.41
(m, 2H), 6.24 (s, 1H), 2.93 (m, 17H), 2.01 (m, 8H).
Example 149
4-(4-{[2-(4-chlorophenyl)cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-i-
ndol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl-
)benzamide
Example 149A
ethyl 2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate
This example was prepared by substituting ethyl
2-oxocyclohexanecarboxylate for
5,5-dimethyl-2-methoxycarbonylcyclohexanone in EXAMPLE 18A.
Example 149B
ethyl 2-(4-chlorophenyl)cyclohex-1-enecarboxylate
This example was prepared by substituting EXAMPLE 149A for EXAMPLE
18A in EXAMPLE 18B.
Example 149C
(2-(4-chlorophenyl)cyclohex-1-enyl)methanol
This example was prepared by substituting EXAMPLE 149B for EXAMPLE
18B in EXAMPLE 18C.
Example 149D
2-(4-chlorophenyl)cyclohex-1-enecarbaldehyde
This example was prepared by substituting EXAMPLE 149C for EXAMPLE
143C in EXAMPLE 143D.
Example 149E
ethyl
2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)cyclohex-1-enyl)methyl-
)piperazin-1-yl)benzoate
The title compound was prepared by substituting EXAMPLE 149D for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 149F
2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)cyclohex-1-enyl)methyl)piper-
azin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 149E for EXAMPLE
143E in EXAMPLE 143F.
Example 149G
4-(4-{[2-(4-chlorophenyl)cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-i-
ndol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl-
)benzamide
This example was prepared by substituting EXAMPLE 149F for EXAMPLE
1E and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d6) .delta. 11.14 (s, 1H), 8.44 (d, 1H),
8.10 (d, 1H), 7.74 (dd, 1H), 7.56 (d, 1H), 7.34 (d, 2H), 7.23 (m,
1H), 7.01 (m, 5H), 6.63 (dd, 1H), 6.34 (d, 1H), 6.22 (m, 2H), 3.74
(m, 1H), 3.03 (m, 7H), 2.67 (m, 5H), 2.07 (m, 11H), 1.67 (m,
7H).
Example 150
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide
Example 150A
methyl 2-(1H-indol-5-yloxy)-4-(piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 26A for EXAMPLE
1C and piperazine for EXAMPLE 1B in EXAMPLE 1D.
Example 150B
methyl
2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dih-
ydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 145E for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 150A for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 150C
2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-
-pyran-3-yl)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 150B for EXAMPLE
143E in EXAMPLE 143F.
Example 150D
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 150C for EXAMPLE
1E and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d6) .delta. 11.00 (s, 1H), 8.42 (d, 1H),
8.07 (d, 1H), 7.67 (dd, 1H), 7.52 (d, 1H), 7.37 (d, 2H), 7.29 (m,
1H), 7.14 (d, 2H), 6.93 (d, 1H), 6.86 (d, 1H), 6.72 (dd, 1H), 6.55
(dd, 1H), 6.31 (s, 1H), 6.15 (d, 1H), 5.85 (m, 3H), 4.11 (s, 2H),
3.00 (m, 8H), 2.82 (s, 2H), 2.73 (m, 3H), 2.23 (m, 8H), 1.57 (m,
2H), 1.18 (s, 6H).
Example 151
4-(4-{[2-(4-chlorophenyl)cyclohept-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H--
indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfony-
l)benzamide
Example 151A
(Z)-methyl
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-enyl)-
methyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 141D for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 150A for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 151B
(Z)-2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-enyl)methyl)-
piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 151A for EXAMPLE
143E in EXAMPLE 143F.
Example 151C
4-(4-{[2-(4-chlorophenyl)cyclohept-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H--
indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfony-
l)benzamide
This example was prepared by substituting EXAMPLE 151B for EXAMPLE
1E and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d6) .delta. 11.06 (s, 1H), 8.48 (d, 1H),
8.11 (d, 1H), 7.74 (dd, 1H), 7.52 (d, 1H), 7.33 (m, 4H), 7.01 (m,
4H), 6.76 (dd, 1H), 6.58 (dd, 1H), 6.34 (s, 1H), 6.14 (d, 1H), 5.75
(s, 1H), 3.69 (m, 1H), 2.96 (m, 6H), 2.71 (m, 2H), 2.36 (m, 8H),
2.21 (s, 5H), 1.98 (m, 2H), 1.63 (m, 8H).
Example 152
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-phen-
oxybenzamide
This compound was made by substituting EXAMPLE 18G for EXAMPLE 1E
and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.43 (m, 1H) 8.18 (d, 1H) 7.82
(dd, 1H) 7.52 (d, 1H) 7.40 (m, 2H) 7.22 (m, 3H) 7.11 (m, 2H) 7.01
(t, 1H) 6.79 (m, 3H) 6.45 (d, 1H) 3.06 (m, 14H) 2.20 (m, 4H) 2.04
(s, 3H) 1.85 (m, 2H) 1.47 (m, 2H) 0.96 (s, 6H).
Example 153
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[2-(dime-
thylamino)ethyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamide
Example 153A
4-(2-(dimethylamino)ethylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting
N,N-dimethylethylenediamine for (tetrahydropyran-4-yl)methylamine
in EXAMPLE 1F.
Example 153B
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[2-(dime-
thylamino)ethyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 153A for EXAMPLE
1F and EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.75 (br s, 1H), 9.78 (br
s, 1H), 9.44 (br s, 1H), 8.66 (t, 1H), 8.49 (d, 1H), 7.83 (d, 1H),
7.70 (m, 2H), 7.51 (m, 4H), 7.38 (d, 2H), 7.33 (m, 1H), 7.24 (d,
2H), 7.18 (d, 1H), 7.02 (dd, 1H), 6.81 (d, 2H), 6.76 (d, 1H), 6.44
(s, 1H), 4.30 (m, 1H), 3.83 (m, 4H), 3.31 (m, 6H), 3.15 (m, 2H),
3.04 (m, 2H), 2.85 (s, 6H).
Example 154
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dime-
thylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2
phenoxybenzamide
Example 154A
4-(3-(dimethylamino)propylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting
N,N-dimethyl-1,3-propanediamine for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 154B
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dime-
thylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 154A for EXAMPLE
1F and EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68 (br s, 1H), 9.38 (br
s, 1H), 8.66 (t, 1H), 8.49 (d, 1H), 7.80 (d, 1H), 7.68 (m, 2H),
7.51 (m, 4H), 7.38 (d, 1H), 7.33 (m, 2H), 7.24 (d, 2H), 7.16 (d,
1H), 7.02 (dd, 1H), 6.81 (d, 2H), 6.76 (d, 1H), 6.43 (s, 1H), 4.25
(m, 1H), 3.50 (m, 4H), 3.30 (m, 4H), 3.12 (m, 6H), 2.78 (s, 6H),
1.95 (m, 2H).
Example 155
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morph-
olin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 7A for EXAMPLE 1F
and EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.70 (br s, 1H), 9.72 (br
s, 1H), 8.68 (t, 1H), 8.49 (d, 1H), 7.81 (d, 1H), 7.70 (m, 2H),
7.51 (m, 4H), 7.37 (d, 2H), 7.33 (m, 1H), 7.24 (d, 2H), 7.15 (d,
1H), 7.03 (dd, 1H), 6.81 (d, 2H), 6.76 (d, 1H), 6.44 (s, 1H), 4.24
(m, 1H), 3.97 (m, 2H), 3.63 (m, 4H), 3.28 (m, 4H), 3.18 (m, 4H),
3.06 (m, 4H), 2.88 (m, 4H), 1.99 (m, 2H).
Example 156
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[4-(dime-
thylamino)butyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamide
Example 156A
4-(4-(dimethylamino)butylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting
N,N-dimethyl-1,4-butanediamine for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 156B
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[4-(dime-
thylamino)butyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 156A for EXAMPLE
1F and EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.70 (br s, 1H), 9.34 (br
s, 1H), 8.63 (t, 1H), 8.48 (d, 1H), 7.79 (d, 1H), 7.70 (m, 2H),
7.51 (m, 4H), 7.39 (d, 2H), 7.33 (m, 1H), 7.24 (d, 2H), 7.12 (d,
1H), 7.01 (dd, 1H), 6.80 (d, 2H), 6.75 (d, 1H), 6.44 (s, 1H), 4.28
(m, 1H), 3.83 (m, 4H), 3.45 (m, 10H), 3.10 (m, 4H), 2.85 (s, 6H),
1.66 (m, 4H).
Example 157
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{-
[1-(phenylsulfonyl)piperidin-4-yl]amino}phenyl)sulfonyl]-2-phenoxybenzamid-
e
Example 157A
tert-butyl
4-(2-nitro-4-sulfamoylphenylamino)piperidine-1-carboxylate
This example was prepared by substituting 1-Boc-4-aminopiperidine
for (tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 157B
3-nitro-4-(piperidin-4-ylamino)benzenesulfonamide
This example was prepared by substituting EXAMPLE 157A for EXAMPLE
1A in EXAMPLE 1B.
Example 157C
3-nitro-4-(1-(phenylsulfonyl)piperidin-4-ylamino)benzenesulfonamide
A mixture of EXAMPLE 157B (84 mg), benzenesulfonyl chloride (46
mg), and triethylamine (101 mg) in CH.sub.2Cl.sub.2 (2 mL) was
stirred for 1 hours. The product was chromatographed on silica gel
with 25% ethyl acetate/hexanes.
Example 157D
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{-
[1-(phenylsulfonyl)piperidin-4-yl]amino}phenyl)sulfonyl]-2-phenoxybenzamid-
e
This example was prepared by substituting EXAMPLE 157C for EXAMPLE
1F and EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68 (br s, 1H), 9.65 (br
s, 1H), 8.42 (s, 1H), 8.19 (d, 1H), 7.78 (m, 2H), 7.70 (m, 4H),
7.51 (m, 5H), 7.37 (m, 3H), 7.19 (m, 3H), 6.94 (dd, 1H), 6.75 (m,
3H), 6.44 (s, 1H), 4.28 (m, 1H), 3.73 (m, 4H), 3.50 (m, 4H), 3.17
(m, 2H), 3.03 (m, 2H), 2.86 (m, 2H), 1.99 (m, 2H), 1.74 (m,
2H).
Example 158
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{-
[1-(quinolin-8-ylsulfonyl)piperidin-4-yl]amino}phenyl)sulfonyl]-2-phenoxyb-
enzamide
Example 158A
3-nitro-4-(1-(quinolin-8-ylsulfonyl)piperidin-4-ylamino)benzenesulfonamide
This example was prepared by substituting quinoline-8-sulfonyl
chloride for benzenesulfonyl chloride in EXAMPLE 157C.
Example 158B
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{-
[1-(quinolin-8-ylsulfonyl)piperidin-4-yl]amino}phenyl)sulfonyl]-2-phenoxyb-
enzamide
This example was prepared by substituting EXAMPLE 158A for EXAMPLE
1F and EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d6) .delta. 11.66 (br s, 1H), 9.10 (dd, 1H),
8.55 (s, 1H), 8.41 (m, 2H), 8.32 (d, 1H), 8.20 (d, 1H), 7.78 (dd,
2H), 7.72 (d, 2H), 7.48 (m, 4H), 7.39 (dd, 2H), 7.33 (m, 1H), 7.17
(m, 3H), 6.95 (dd, 1H), 6.76 (m, 3H), 6.42 (s, 1H), 4.35 (m, 1H),
3.90 (d, 2H), 3.77 (m, 2H), 3.34 (m, 6H), 2.99 (m, 4H), 1.97 (m,
2H), 1.65 (m, 2H).
Example 159
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-phenoxy-N-({4-
-{[1-(phenylsulfonyl)piperidin-4-yl]amino}-3-[(trifluoromethyl)sulfonyl]ph-
enyl}sulfonyl)benzamide
Example 159A
(2-fluorophenyl)(trifluoromethyl)sulfane
Methyl viologen hydrochloride (1.17 g) in N,N-dimethylformamide (80
mL) at 25.degree. C. was saturated with trifluoromethyl iodide,
treated with 2-fluorobenzenethiol (9.7 mL) and triethylamine (20
mL), stirred for 24 hours, diluted with water (240 mL) and
extracted with diethyl ether. The extract was washed with 1M NaOH,
saturated ammonium chloride and brine and concentrated.
Example 159B
1-fluoro-2-(trifluoromethylsulfonyl)benzene
Example 159A
17.346 g) in 1:1:2 carbon tetrachloride:acetonitrile:water (800 mL
at 25.degree. C. was treated with sodium periodate (56.8 g) and
ruthenium(III) chloride hydrate (183 mg), stirred for 18 hours,
diluted with dichloromethane (100 mL) and filtered through
diatomaceous earth (Celite.RTM.). The filtrate was washed with
saturated sodium bicarbonate and extracted with dichloromethane.
The extract was washed with brine and dried (MgSO.sub.4), filtered
and concentrated. The concentrate was filtered through silica
gel.
Example 159C
4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide
EXAMPLE 159B (37.3 g) in chlorosulfonic acid (32.8 mL) at
120.degree. C. was stirred for 18 hours, cooled to 25.degree. C.
and pipetted onto crushed ice. The mixture was extracted with ethyl
acetate, and the extract was washed with water and brine and dried
(MgSO.sub.4), filtered and concentrated. The crude product was
taken up in isopropanol (706 mL) at -78.degree. C., treated with
ammonium hydroxide (98 mL) over 1 hour, stirred for 1 hour,
quenched with 6M HCl (353 mL), warmed to 25.degree. C. and
concentrated. The concentrate was mixed with water and extracted
with ethyl acetate. The extract was dried over MgSO.sub.4, filtered
and concentrated. The concentrate was recrystallized from ethyl
acetate/hexane.
Example 159D
tert-butyl
4-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)piperidin-
e-1-carboxylate
This example was prepared by substituting 1-Boc-4-aminopiperidine
for (tetrahydropyran-4-yl)methylamine and EXAMPLE 159C for
4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 1F.
Example 159E
4-(piperidin-4-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide
This example was prepared by substituting EXAMPLE 159D for EXAMPLE
1A in EXAMPLE 1B.
Example 159F
4-(1-(phenylsulfonyl)piperidin-4-ylamino)-3-(trifluoromethylsulfonyl)benze-
nesulfonamide
This example was prepared by substituting EXAMPLE 159E for EXAMPLE
157B in EXAMPLE 157C.
Example 159G
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-phenoxy-N-({4-
-{[1-(phenylsulfonyl)piperidin-4-yl]amino}-3-[(trifluoromethyl)sulfonyl]ph-
enyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 159F for EXAMPLE
1F and EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.72 (br s, 1H), 9.70 (br
s, 1H), 8.07 (s, 1H), 7.67-7.82 (m, 7H), 7.52 (d, 2H), 7.47 (d,
2H), 7.36 (m, 3H), 7.24 (dd, 2H), 7.14 (d, 1H), 7.01 (m, 1H), 6.78
(d, 2H), 6.72 (m, 2H), 6.44 (d, 1H), 4.27 (m, 1H), 3.73 (m, 4H),
3.46 (m, 4H), 3.17 (m, 2H), 3.03 (m, 2H), 2.87 (m, 2H), 1.97 (m,
2H), 1.64 (m, 2H).
Example 160
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-phenoxy-N-({4-
-{[1-(quinolin-8-ylsulfonyl)piperidin-4-yl]amino}-3-[(trifluoromethyl)sulf-
onyl]phenyl}sulfonyl)benzamide
Example 160A
4-(1-(quinolin-8-ylsulfonyl)piperidin-4-ylamino)-3-(trifluoromethylsulfony-
l)benzenesulfonamide
This example was prepared by substituting EXAMPLE 159E for EXAMPLE
157B and quinoline-8-sulfonyl chloride for benzenesulfonyl chloride
in EXAMPLE 157C.
Example 160B
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-phenoxy-N-({4-
-{[1-(quinolin-8-ylsulfonyl)piperidin-4-yl]amino}-3-[(trifluoromethyl)sulf-
onyl]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 160A for EXAMPLE
1F and EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.74 (br s, 1H), 9.50 (br
s, 1H), 9.08 (dd, 1H), 8.55 (s, 1H), 8.39 (d, 1H), 8.33 (d, 1H),
8.06 (s, 1H), 7.82 (dd, 2H), 7.70 (m, 1H), 7.50 (m, 3H), 7.40 (dd,
2H), 7.33 (m, 1H), 7.21 (m, 2H), 7.08 (m, 2H), 6.99 (dd, 1H), 6.95
(s, 1H), 6.78 (d, 1H), 6.73 (m, 2H), 6.42 (s, 1H), 4.35 (m, 1H),
3.75 (m, 4H), 3.34 (m, 6H), 3.05 (m, 4H), 1.93 (m, 2H), 1.55 (m,
2H.
Example 161
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[(S)-3-(-
dimethylamino)-1-thien-2-ylpropyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxy-
benzamide
Example 161A
(S)-3-(benzyloxycarbonylamino)-3-(thiophen-2-yl)propanoic acid
(S)-3-amino-3-(thiophen-2-yl)propanoic acid (0.894 g) and
benzyloxycarbonyl chloride 0.980 g) were stirred in 2M NaOH (8 mL)
and dioxane (26 mL) at 0.degree. C. for 24 hours. The reaction
mixture was acidified with concentrated aqueous HCl, extracted
twice with ethyl acetate, and the extracts were dried over
MgSO.sub.4, filtered, concentrated, and chromatographed on silica
gel with 50% ethyl acetate/hexanes.
Example 161B
(S)-benzyl
3-(dimethylamino)-3-oxo-1-(thiophen-2-yl)propylcarbamate
This example was prepared by substituting EXAMPLE 161A for EXAMPLE
1E and dimethylamine for EXAMPLE 1F in EXAMPLE 1G.
Example 161C
(S)--N.sup.1,N.sup.1-dimethyl-3-(thiophen-2-yl)propane-1,3-diamine
A solution of EXAMPLE 161B (400 mg) and borane in tetrahydrofuran
(1M, 2.5 mL) in tetrahydrofuran (6 mL) was stirred for 24 hours.
The reaction was quenched with methanol, taken up in pH 7 buffer
solution, and extracted three times with ethyl acetate. The
combined extracts were washed with brine and concentrated. The
crude product was taken up in HBr in acetic acid (1.1 mL) and
stirred for 2 hours. The reaction was poured into CH.sub.2Cl.sub.2
(50 mL) and washed with 1M NaOH solution. The organic layer was
dried over Na.sub.2SO.sub.4, and concentrated.
Example 161D
(S)-4-(3-(dimethylamino)-1-(thiophen-2-yl)propylamino)-3-nitrobenzenesulfo-
namide
This example was prepared by substituting EXAMPLE 161C for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 161E
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[(1S)-3--
(dimethylamino)-1-thien-2-ylpropyl]amino}-3-nitrophenyl)sulfonyl]-2-phenox-
ybenzamide
This example was prepared by substituting EXAMPLE 161D for EXAMPLE
1F and EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-ddD.sub.2O) .delta. 11.72 (br s, 1H), 9.51
(br s, 1H), 8.60 (d, 1H), 8.48 (s, 1H), 7.75 (d, 1H), 7.70 (m, 1H),
7.51 (m, 4H), 7.38 (d, 2H), 7.32 (m, 1H), 7.25 (d, 1H), 7.16 (m,
3H), 7.06 (d, 1H), 6.92 (m, 1H), 6.75 (d, 3H), 6.44 (d, 1H), 5.31
(m, 1H), 4.30 (m, 1H), 3.54 (m, 8H), 3.20 (m, 2H), 3.07 (m, 2H),
2.80 (s, 6H), 2.35 (m, 2H).
Example 162
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(thien-2-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide
Example 162A
3-nitro-4-(thiophen-2-ylmethylamino)benzenesulfonamide
This example was prepared by substituting 2-thiophenemethylamine
for (tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 162B
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(thien-2-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 162B for EXAMPLE
1F and EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6/D.sub.2O) .delta. 11.67 (br s, 1H),
9.55 (br s, 1H), 9.11 (t, 1H), 8.47 (s, 1H), 7.70 (m, 2H), 7.51 (m,
4H), 7.38 (d, 2H), 7.33 (m, 1H), 7.15 (m, 4H), 7.02 (d, 1H), 6.94
(m, 1H), 6.74 (d, 3H), 6.44 (d, 1H), 4.87 (m, 2H), 4.37 (m, 1H),
3.34 (m, 8H), 3.03 (m, 2H).
Example 163
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-phenoxy-N-({4-
-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phen-
yl}sulfonyl)benzamide
Example 163A
4-((tetrahydro-2H-pyran-4-yl)methylamino)-3-(trifluoromethylsulfonyl)benze-
nesulfonamide
This example was prepared by substituting EXAMPLE 159C for
4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 1F.
Example 163B
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-phenoxy-N-({4-
-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phen-
yl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 163A for EXAMPLE
1F and EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.71 (br s, 1H), 8.10 (d,
1H), 7.86 (d, 1H), 7.10 (m, 1H), 7.50 (m, 4H), 7.37 (m, 2H), 7.27
(m, 3H), 7.08 (m, 1H), 7.03 (dd, 1H), 6.95 (d, 1H), 6.82 (d, 1H),
6.76 (d, 1H), 6.43 (s, 1H), 4.35 (m, 1H), 3.84 (dd, 2H), 3.35 (m,
8H), 3.22 (m, 2H), 3.03 (m, 2H), 2.86 (m, 2H), 1.86 (m, 1H), 1.55
(m, 2H), 1.26 (m, 2H).
Example 164
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{-
[2-(1H-1,2,3-triazol-1-yl)ethyl]amino}phenyl)sulfonyl]-2-phenoxybenzamide
Example 164A
4-(2-hydroxyethylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting 2-aminoethanol for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 164B
4-(2-(tert-butyldimethylsilyloxy)ethylamino)-3-nitrobenzenesulfonamide
EXAMPLE 164A (131 mg), t-butyldimethylsilyl chloride (75 mg) and
imidazole (68 mg) were stirred in CH.sub.2Cl.sub.2 (17 mL) for 24
hours. The reaction mixture was chromatographed on silica gel with
10% ethyl acetate/hexanes.
Example 164C
N-(4-(2-(tert-butyldimethylsilyloxy)ethylamino)-3-nitrophenylsulfonyl)-4-(-
4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 164B for EXAMPLE
1F in EXAMPLE 1G.
Example 164D
2-(4-(N-(4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxyben-
zoyl)sulfamoyl)-2-nitrophenylamino)ethyl
4-methylbenzenesulfonate
EXAMPLE 164C (150 mg) and concentrated aqueous HCl (0.020 mL) were
stirred in tetrahydrofuran (1 mL) and methanol (1 mL) for 1 hours.
The mixture was filtered through a short silica gel column. The
product was taken up in CH.sub.2Cl.sub.2 (1 mL) and to it was added
triethylamine (0.074 mL) and p-toluenesulfonic anhydride (58 mg)
and the reaction was stirred for 24 hours. The reaction mixture was
chromatographed on silica gel with 10% ethyl acetate/hexanes.
Example 164E
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{-
[2-(1H-1,2,3-triazol-1-yl)ethyl]amino}phenyl)sulfonyl]-2-phenoxybenzamide
Example 164D (30 mg), 1,2,3-triazole (7 mg) and cesium carbonate
(55 mg were stirred in N,N-dimethylformamide (0.2 mL) for 24 hours.
The reaction was quenched with ammonium chloride, and was extracted
twice with ethyl acetate. The combined organic layers were dried
over MgSO.sub.4, filtered, and concentrated. The product was
purified by preparative HPLC using a C18 column, 250.times.50 mm,
10, and eluting with a gradient of 20-100% CH.sub.3CN vs. 0.1%
trifluoroacetic acid in water, giving the product as a
trifluoroacetate salt. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.75 (br s, 1H), 9.62 (br s,
1H), 8.66 (dd, 1H), 8.44 (d, 1H), 8.18 (s, 1H), 7.72 (m, 3H), 7.51
(m, 5H), 7.36 (m, 3H), 7.19 (dd, 2H), 7.06 (m, 1H), 6.93 (dd, 1H),
6.75 (d, 2H), 6.45 (s, 1H), 4.70 (t, 2H), 3.93 (dt, 2H), 3.61 (m,
4H), 3.22 (m, 2H), 3.01 (m, 2H), 2.84 (m, 2H).
Example 165
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{-
[2-(2H-1,2,3-triazol-2-yl)ethyl]amino}phenyl)sulfonyl]-2-phenoxybenzamide
This example was prepared in the same reaction as that for EXAMPLE
164E. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.75 (br s, 1H), 9.70 (br s, 1H), 8.67 (dd, 1H), 8.42 (s, 1H),
7.80 (s, 1H), 7.75 (m, 1H), 7.68 (d, 2H), 7.51 (m, 5H), 7.37 (m,
3H), 7.18 (dd, 2H), 6.97 (m, 1H), 6.92 (dd, 1H), 6.75 (d, 2H), 6.46
(s, 1H), 4.76 (t, 2H), 3.93 (dt, 2H), 3.67 (m, 4H), 3.22 (m, 2H),
3.03 (m, 2H), 2.84 (m, 2H).
Example 166
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dime-
thylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(2-naphthyloxy)benzamide
This example was prepared by substituting EXAMPLE 35B for EXAMPLE
27G and EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.83 (br s, 1H), 9.46
(br s, 1H), 8.53 (t, 1H), 8.40 (s, 1H), 7.81 (d, 2H), 7.71 (m, 1H),
7.63 (m, 2H), 7.51 (m, 5H), 7.37 (m, 4H), 7.17 (d, 1H), 7.03 (s,
1H), 6.82 (d, 2H), 6.57 (d, 1H), 4.27 (m, 1H), 3.62 (m, 6H), 3.39
(m, 2H), 3.09 (m, 2H), 2.80-3.25 (m, 6H), 2.79 (s, 6H), 1.91 (m,
2H).
Example 167
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{-
[2-(2-oxopyridin-1(2H)-yl)ethyl]amino}phenyl)sulfonyl]-2-phenoxybenzamide
This example was prepared by substituting pyridin-2-ol for
1,2,3-triazole in EXAMPLE 164E. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.70 (br s, 1H), 9.65 (br s,
1H), 8.75 (t, 1H), 8.44 (d, 1H), 7.72 (d, 2H), 7.64 (d, 1H), 7.51
(m, 5H), 7.37 (m, 3H), 7.20 (m, 3H), 6.95 (t, 1H), 6.77 (d, 3H),
6.46 (s, 1H), 6.41 (d, 1H), 6.21 (t, 1H), 4.31 (m, 1H), 4.17 (t,
2H), 3.74 (dt, 2H), 3.60 (m, 6H), 3.20 (m, 2H), 3.03 (m, 2H), 2.87
(m, 2H).
Example 168
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{-
[2-(pyridin-2-yloxy)ethyl]amino}phenyl)sulfonyl]-2-phenoxybenzamide
This example was prepared by substituting pyridin-2-ol for
1,2,3-triazole in EXAMPLE 164E. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.71 (br s, 1H), 9.65 (br s,
1H), 8.84 (t, 1H), 8.44 (d, 1H), 8.19 (d, 1H), 7.74 (m, 3H), 7.51
(m, 5H), 7.37 (m, 3H), 7.20 (m, 3H), 7.00 (dd, 1H), 6.92 (t, 1H),
6.83 (d, 1H), 6.76 (m, 2H), 6.45 (d, 1H), 4.56 (t, 2H), 4.31 (m,
1H), 3.81 (dt, 2H), 3.71 (m, 6H), 3.23 (m, 2H), 3.04 (m, 2H), 2.89
(m, 2H).
Example 169
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(2-pyridin-4-ylethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide
Example 169A
3-nitro-4-(2-(pyridin-4-yl)ethylamino)benzenesulfonamide
This example was prepared by substituting
2-(pyridin-4-yl)ethanamine for (tetrahydropyran-4-yl)methylamine in
EXAMPLE 1E.
Example 169B
4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[-
(2-pyridin-4-ylethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide
This example was prepared by substituting EXAMPLE 169A for EXAMPLE
1F and EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.71 (br s, 1H), 9.70 (br s,
1H), 8.69 (d, 1H), 8.61 (t, 1H), 8.46 (s, 1H), 7.79 (dd, 1H), 7.72
(d, 3H), 7.51 (m, 5H), 7.37 (d, 2H), 7.32 (d, 1H), 7.21 (m, 3H),
6.95 (t, 1H), 6.78 (d, 2H), 6.75 (d, 1H), 6.44 (d, 1H), 4.23 (m,
1H), 3.76 (dt, 2H), 3.63 (m, 4H), 3.13 (t, 2H), 2.76-3.24 (m,
6H).
Example 170
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-{[3-(dimethylamino)propyl]amino}-3-[(trifluoromethyl)sulfonyl]-
phenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide
Example 170A
4-(3-(dimethylamino)propylamino)-3-(trifluoromethylsulfonyl)benzenesulfona-
mide
This example was prepared by substituting
N,N-dimethyl-1,3-propanediamine for
(tetrahydropyran-4-yl)methylamine and EXAMPLE 159C for
4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 1F.
Example 170B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-{[3-(dimethylamino)propyl]amino}-3-[(trifluoromethyl)sulfonyl]-
phenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 170A for EXAMPLE
1F and EXAMPLE 26C for EXAMPLE 27G in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.42 (br s, 1H), 11.17 (s,
1H), 9.37 (br s, 1H), 8.22 (d, 1H), 7.98 (d, 1H), 7.52 (d, 1H),
7.35-7.45 (m, 4H), 7.19 (d, 1H), 7.08 (m, 3H), 6.85 (dd, 1H), 6.67
(dd, 1H), 6.40 (d, 1H), 6.19 (d, 1H), 3.55 (m, 8H), 3.04 (m, 4H),
2.77 (s, 6H), 2.72 (m, 2H), 2.17 (m, 2H), 2.00 (m, 2H), 1.88 (m,
2H), 1.44 (m, 2H), 0.93 (s, 6H).
Example 171
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-{[3-(dimethylamino)propyl]amino}-3-(trifluoromethyl)phenyl]sul-
fonyl}-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
27G and EXAMPLE 92B for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.19 (br s, 1H), 9.33 (br
s, 1H), 7.94 (d, 1H), 7.85 (d, 1H), 7.54 (d, 1H), 7.35-7.45 (m,
4H), 7.20 (d, 1H), 7.07 (d, 2H), 6.88 (dd, 2H), 6.67 (dd, 1H), 6.58
(m, 1H), 6.41 (s, 1H), 6.18 (s, 1H), 3.57 (m, 6H), 3.33 (m, 2H),
3.09 (m, 2H), 3.04 (m, 2H), 2.77 (s, 6H), 2.74 (m, 2H), 2.17 (m,
2H), 2.00 (m, 2H), 1.87 (m, 2H), 1.44 (m, 2H), 0.93 (s, 6H).
Example 172
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex
1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-cyano-4-{[3-(dimethylamino)propyl]-
amino}phenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
27G and EXAMPLE 90B for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.19 (br s, 1H), 9.38 (br
s, 1H), 7.98 (s, 1H), 7.81 (d, 1H), 7.55 (d, 1H), 7.35-7.45 (m,
4H), 7.20 (s, 1H), 7.16 (t, 1H), 7.07 (d, 2H), 6.86 (dd, 2H), 6.68
(dd, 1H), 6.41 (s, 1H), 6.18 (s, 1H), 3.57 (m, 6H), 3.31 (m, 2H),
3.09 (m, 2H), 3.04 (m, 2H), 2.77 (s, 6H), 2.74 (m, 2H), 2.17 (m,
2H), 2.00 (m, 2H), 1.87 (m, 2H), 1.44 (m, 2H), 0.93 (s, 6H).
Example 173
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiper-
idin-4-yl)amino]phenyl}sulfonyl)benzamide
Example 173A
tert-butyl 1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylcarbamate
A mixture of tert-butyl piperidin-4-ylcarbamate (45 g) and
dihydro-2H-pyran-4(3H)-one (24.74 g) in dichloromethane (1000 mL)
was treated with sodium triacetoxyborohydride (61.9 g), stirred at
room temperature for 16 hours, washed with 1M sodium hydroxide and
dried with anhydrous sodium sulfate, filtered and concentrated. The
concentrate was flash column chromatographed on silica gel with
10-20% methanol/dichloromethane.
Example 173B
1-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine
A solution of EXAMPLE 173A (52.57 g) in dichloromethane (900 mL)
was treated with 4M HCl (462 mL), mixed vigorously at room
temperature for 16 hours and concentrated.
Example 173C
3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)benzenesulfonam-
ide
A mixture of EXAMPLE 173B (22.12 g), water (43 mL), and
triethylamine (43.6 mL) in 1,4-dioxane (300 mL) was stirred at room
temperature until EXAMPLE 173B completely dissolved. The solution
was then treated with 4-chloro-3-nitrobenzenesulfonamide, heated at
90.degree. C. for 16 hours, cooled and concentrated. 10% methanol
in dichloromethane was added, and the solution was stirred
vigorously at room temperature until a fine suspension existed and
the mixture was filtered.
Example 173D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiper-
idin-4-yl)amino]phenyl}sulfonyl)benzamide
A mixture of EXAMPLE 26C (3.95 g), EXAMPLE 173C (2.66 g),
1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride
(2.66 g), and 4-dimethylaminopyridine (0.846 g) in dichloromethane
(70 mL) and acetonitrile (20 mL) was stirred at 35.degree. C. for
24 hours, cooled and chromatographed on silica gel with 0-10%
methanol in ethyl acetate, then 10% methanol in 1:1 ethyl
acetate/dichloromethane. The combined fractions were concentrated,
dissolved in of 5% methanol/ethyl acetate (1.5 L), and the solution
was washed with saturated NaH.sub.2PO.sub.4 solution and brine and
dried over Na.sub.2SO.sub.4, filtered, concentrated to 300 mL,
cooled, and filtered. The remaining solution was concentrated
partway and filtered again to isolate more product. .sup.1H NMR
(300 MHz, dimethysulfoxide-d.sub.6) .delta. 11.17 (brs, 1H), 10.70
(br s, 1H), 8.60 (d, 1H), 8.20 (br d, 1H), 7.88 (dd, 1H), 7.50 (d,
1H), 7.39 (m, 2H), 7.33 (d, 2H), 7.16 (m, 2H), 7.03 (d, 2H), 6.85
(dd, 1H), 6.65 (dd, 1H), 6.39 (s, 1H), 6.14 (s, 1H), 3.97 (m, 4H),
3.44 (m, 4H), 3.04 (m, 6H), 2.75 (m, 2H), 2.14 (m, 8H), 1.95 (m,
6H), 1.66 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 174
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(l
1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitro-
phenyl}sulfonyl)benzamide
Example 174A
4-(4-methylpiperazin-1-ylamino)-3-nitrobenzenesulfonamide
A mixture of 4-chloro-3-nitrobenzenesulfonamide (1 g),
4-methylpiperazin-1-amine dihydrochloride (1 g) and
N.sup.1,N.sup.1,N.sup.2,N.sup.2-tetramethylethane-1,2-diamine (3
mL) in dioxane (10 mL) was refluxed for 12 hours, cooled to ambient
temperature and filtered. The filtrate was added to a silica gel
column (Analogix, SF65-200g) and purified by eluting with 1-5%
methanol/dichloromethane).
Example 174B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide
A mixture of EXAMPLE 26C (0.108 g), EXAMPLE 174A (64 mg),
1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride
(0.08 g) and 4-dimethylaminopyridine (0.08 g) in dichloromethane (3
mL) was stirred at ambient temperature overnight and concentrated.
The concentrate was added to a preparative HPLC column and eluted
with 20-100% acetonitrile/water with 0.1% trifluoroacetic acid. The
trifluoroacetic acid salt solution was neutralized with NaHCO.sub.3
and extracted with dichloromethane. This solution was washed with
saturated NaHCO.sub.3, dried over Na.sub.2SO.sub.4, and filtered
and concentrated. .sup.1H NMR (500 MHz, dimethysulfoxide-d.sub.6)
.delta. 11.14 (s, 1H), 9.17 (s, 1H), 8.52 (s, 1H), 7.83 (m, 1H),
7.53 (m, 2H), 7.36 (m, 4H), 7.12 (s, 1H), 7.03 (d, 2H), 6.83 (m,
1H), 6.62 (m, 1H), 6.38 (s, 1H), 6.13 (m, 1H), 5.76 (s, 2H), 2.85
(m, 12H), 2.35 (m, 4H), 2.14 (m, 6H), 1.94 (m, 2H), 1.38 (m, 2H),
0.92 (s, 6H).
Example 175
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4--
yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)benzamide
Example 175A
1-(4'-chlorobiphenyl-2-yl)ethanone
A mixture of 1-(2-bromophenyl)ethanone (3.1 g, 15.57
mmol).sub.4-chlorophenylboronic acid (2.92 g),
(Ph.sub.3P).sub.2PdCl.sub.2 (bis(triphenylphosphine)palladium(II)
dichloride) (1.202 g) and Na.sub.2CO.sub.3 (3.30 g) in
dimethoxyethane-ethanol-water (7:2:3, 50 mL) was heated at
100.degree. C. for 3 hours and concentrated. The concentrate was
suspended in dichloromethane (30 mL) and the insoluble material was
removed by filtration. The filtrate was loaded onto a silica gel
column, eluted with 0%-50% dichloromethane in hexane to provide the
title compound.
Example 175B
tert-butyl
4-(1-(4'-chlorobiphenyl-2-yl)ethyl)piperazine-1-carboxylate
Example 175A
1.9 g) was dissolved in dichloromethane (3 mL) and titanium(IV
chloride (9.06 mL, 9.06 mmol) was added. The solution was cooled to
0.degree. C. and tert-butyl piperazine-1-carboxylate (3.07 g) was
added. The resulting mixture was stirred at ambient temperature for
3 hours and NaCNBH.sub.3 (0.828 g) in methanol (5 mL) was added.
The resulting mixture was stirred at room temperature overnight and
neutralized by aqueous NaOH, and then concentrated. To the
concentrate was added ethyl acetate and the insoluble material was
filtered off. The organic layer was washed with water and
concentrated. The concentrate was dissolved in a mixture of
methanol-trifluoroacetic acid-dimethysulfoxide, loaded onto a
reverse phase C18 column, and eluted with 0-80% acetonitrile in
0.1% trifluoroacetic acid water over 70 minutes.
Example 175C
1-(1-(4'-chlorobiphenyl-2-yl)ethyl)piperazine
To a solution of EXAMPLE 175B (650 mg) in dichloromethane (6 mL)
was added trifluoroacetic acid (6 mL) at 0.degree. C. The reaction
mixture was stirred at 0.degree. C. for 50 minutes and
concentrated. The concentrate was dissolved in dichloromethane,
washed with aqueous NaHCO.sub.3 and the organic layer was dried
over Na.sub.2SO.sub.4, and concentrated.
Example 175D
ethyl
2-(1H-indol-4-yloxy)-4-(4-(1-(4'-chlorobiphenyl-2-yl)ethyl)piperazin-
-1-yl)benzoate
EXAMPLE 175C (193 mg) and ethyl
2-(1H-indol-4-yloxy)-4-fluorobenzoate (211 mg) in dimethysulfoxide
(15 mL) was treated with potassium hydrogen phosphate (168 mg) at
135.degree. C. overnight and cooled. The reaction mixture was
diluted with dichloromethane and washed with water. The organic
layer was concentrated. The concentrate was dissolved in
dichloromethane, loaded onto a silica gel column, eluted with
0%-10% 10 M ammonia methanol in dichloromethane.
Example 175E
2-(1H-indol-4-yloxy)-4-(4-(1-(4'-chlorobiphenyl-2-yl)ethyl)piperazin-1-yl)-
benzoic acid
EXAMPLE 175D (200 mg) in tetrahydrofuran (10 mL) and methanol (10
mL) was treated with 10% NaOH (3 mL) at 50.degree. C. overnight and
neutralized with HCl. The mixture was concentrated and the
concentrate was taken up in water and extracted with
dichloromethane. The organic layer was dried over Na.sub.2SO.sub.4
and concentrated.
Example 175F
4-(4-(1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl)piperazin-1-yl)-2-(1H-indol-4--
yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfony-
l)benzamide
To a mixture of EXAMPLE 175E (66 mg),
3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide
(75 mg) and 4-dimethylaminopyridine (58.4 mg) in dichloromethane (5
mL) was added 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide
hydrochloride (45.8 mg). The mixture was stirred at ambient
temperature overnight and concentrated. The concentrate was
purified by RP HPLC (10-70% acetonitrile in 0.1% trifluoroacetic
acid water/70 minutes). The desired fractions were concentrated to
remove acetonitrile and the concentrate was diluted with
dichloromethane and neutralized with aqueous NaHCO.sub.3. The
dichloromethane layer was dried over Na.sub.2SO.sub.4 and
concentrated to provide the title compound. .sup.1H NMR (500 MHz,
dimethysulfoxide-d.sub.6) .delta. ppm 11.31 (1H, s), 11.25 (1H, s),
8.62 (1H, t), 8.50 (1H, d), 7.68 (1H, dd), 7.53 (2H, d), 7.46 (2H,
d), 7.37 (1H, t), 7.24-7.31 (4H, m), 7.17 (1H, d), 7.12 (1H, dd),
7.07 (1H, d), 6.96 (1H, t), 6.69 (1H, dd), 6.42 (1H, d), 6.26 (2H,
s), 3.85 (2H, dd), 3.21-3.33 (5H, m), 3.01 (4H, s), 2.29-2.39 (2H,
m), 2.15-2.22 (2H, m), 1.83-1.94 (1H, m), 1.57-1.68 (2H, m),
1.22-1.31 (2H, m), 1.17 (3H, d).
Example 176
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfo-
nyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-(1H-indol-4-yloxy)benzamide
Example 176A
4-((4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide
A mixture of 4-chloro-3-nitrobenzenesulfonamide,
4-(aminomethyl)tetrahydro-2H-pyran-4-amine bis-hydrochloric acid
salt and triethylamine in dioxane (10 mL) was heated at 110.degree.
C. overnight. After cooling, the reaction mixture was diluted with
water (10 mL), and the solid was filtered to give the title
compound.
Example 176B
N-((4-(((4-aminotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfo-
nyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piper-
azin-1-yl)-2-(1H-indol-4-yloxy)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 55B for EXAMPLE
1F and EXAMPLE 176A
(4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide)
for EXAMPLE 1G in EXAMPLE 1H. .sup.1H NMR (500 MHz,
dimethysulfoxide-d.sub.6) .delta. 11.15 (s, 1H), 8.51 (s, 1H), 8.45
(d, J=2.14 Hz, 1H), 7.70 (dd, J=9.0, 1.98 Hz, 1H), 7.59 (d, J=8.85
Hz, 1H), 7.34 (d, J=8.24 Hz, 2H), 7.22 (t, J=2.59 Hz, 1H),
7.11-7.12 (m, 2H), 7.04 (d, J=8.54 Hz, 2H), 6.93 (t, J=7.78 Hz,
1H), 6.62 (dd, J=9.0, 1.98 Hz, 1H), 6.34 (d, J=7.63 Hz, 1H),
6.20-6.23 (m, 2H), 3.55-3.70 (m, 6H), 2.96 (m, 3H), 2.71 (s, 2H),
2.16 (m, 6H), 1.95 (m, 2H), 1.70-1.74 (m, 2H), 1.55-1.59 (m, 2H),
1.37-1.39 (m, 2H), 0.92 (s, 6H).
Example 177
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)-
amino]phenyl}sulfonyl)benzamide
A mixture of EXAMPLE 26C (2.85 g, 10 mmol), EXAMPLE 1F (1.577 g, 5
mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide
hydrochloride (1.917 g, 10 mmol), 4-(dimethylamino)pyridine (1.222
g, 10 mmol), and triethyl amine (2.8 mL, 20 mmol) was treated with
CH.sub.2Cl.sub.2 (20 mL) and N,N-dimethylformamide (2 mL). The
reaction mixture was stirred over night. The solvent was removed,
and the residue was partitioned between water and ethyl acetate.
The organic layers were washed with 1% HCl twice, then with sat
NaHCO.sub.3, brine, dried, filtered, and concentrated The residue
was purified by reverse phase HPLC on a C18 column using a gradient
of 40-60% acetonitrile/0.1% TFA in water to give the title compound
as the trifluoroacetate salt. The TFA salt was dissolved in
dichloromethane (6 ml) and washed with 50% aqueous NaHCO.sub.3. The
organic layer was dried over anhydrous Na.sub.2SO.sub.4 and
concentrated to give the title compound. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.18 (s, 2H), 8.59-8.64 (m,
2H), 7.80 (dd, 1H), 7.52 (d, 1H), 7.39-7.42 (m, 2H), 7.33 (d, 2H),
7.16 (d, 1H), 7.10 (d, 1H), 7.03 (d, 2H), 6.8 (dd, 1H), 6.65 (dd,
1H), 6.40)s, 1H), 6.14 (d, 1H), 3.85 (dd, 2H), 3.24-3.32 (m, 4H),
3.03 (s, 3H), 2.73 (s, 2H), 2.12-2.17 (m, 5H), 1.68-1.94 (m, 3H),
1.61 (d, 2H), 1.37 (t, 2H), 1.24-1.27 (m, 2H), 0.92 (s, 6H).
Example 178
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-
-3-nitrophenyl}sulfonyl)benzamide
Example 178A
Trans-4-(4-morpholinocyclohexylamino)-3-nitrobenzenesulfonamide
This EXAMPLE was prepared by substituting
4-amino-N-morpholinylpiperidine for
1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 178B
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-
-3-nitrophenyl}sulfonyl)benzamide
The title compound was prepared as in EXAMPLE 177 by replacing
EXAMPLE 1F with EXAMPLE 178A. .sup.1H NMR (500 MHz,
pyridine-d.sub.5) .delta. 12.29 (s, 1H), 9.29 (d, J=2.1 Hz, 1H),
8.37 (d, J=7.6 Hz, 1H), 8.32 (dd, J=9.3, 2.3 Hz, 1H), 8.18 (d,
J=8.8 Hz, 1H), 7.52-7.57 (m, 2H), 7.39-7.47 (m, 3H), 7.10 (dd,
J=8.7, 2.3 Hz, 1H), 7.05-7.08 (m, 2H), 6.90 (d, J=9.5 Hz, 1H), 6.74
(dd, J=9.0, 2.3 Hz, 1H), 6.59-6.63 (m, 1H), 6.55 (d, J=2.4 Hz, 1H),
3.72-3.78 (m, 4H), 3.33-3.43 (m, 1H), 2.99-3.09 (m, 4H), 2.76 (s,
2H), 2.46-2.54 (m, 4H), 2.16-2.29 (m, 3H), 2.09-2.14 (m, 4H), 2.05
(d, J=11.9 Hz, 2H), 1.97 (d, J=1.8 Hz, 2H), 1.87 (d, J=11.6 Hz,
2H), 1.19-1.42 (m, 6H), 0.93 (s, 6H).
Example 179
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sul-
fonyl)benzamide
Example 179A
4-(2-methoxyethylamino)-3-nitrobenzenesulfonamide
This EXAMPLE was prepared by substituting 2-methoxyethylamine for
1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 179B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sul-
fonyl)benzamide
The title compound was prepared as in EXAMPLE 177 by replacing
EXAMPLE 1F with EXAMPLE 179A. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.20 (br. s, 1H) 11.15 (s, 1H) 8.59 (m, 2H) 7.81 (dd, 1H)
7.50 (d, 1H) 7.36 (m, 4H) 7.08 (m, 4H) 6.85 (dd, 1H) 6.65 (dd, 1H)
6.38 (m, 1H) 6.14 (m, 1H) 3.58 (m, 4H) 3.30 (s, 3H) 3.03 (m, 4H)
2.73 (s, 2H) 2.15 (m, 6H) 1.96 (s, 2H) 1.38 (t, 2H) 0.92 (s,
6H).
Example 180
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylme-
thyl]amino}phenyl)sulfonyl]benzamide
Example 180A
(R)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonamide
and
(S)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonami-
de
This EXAMPLE was prepared by substituting
(tetrahydro-2H-pyran-3-yl)methanamine for
1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 180B
(S)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonamide
The racemic mixture of EXAMPLE 180A was resolved by chiral SFC on
an AD column (21 mm i.d..times.250 mm in length) using a gradient
of 10-30% 0.1% diethylamine methanol in CO.sub.2 over 15 min (oven
temperature: 40.degree. C.; flow rate: 40 mL/min) to provide the
title compound.
Example 180C
(R)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonamide
The racemic mixture of EXAMPLE 180A was resolved by chiral SFC on
an AD column (21 mm i.d..times.250 mm in length) using a gradient
of 10-30% 0.1% diethylamine methanol in CO.sub.2 over 15 min (oven
temperature: 40.degree. C.; flow rate: 40 mL/min) to provide the
title compound.
Example 180D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylme-
thyl]amino}phenyl)sulfonyl]benzamide
The title compound was prepared as in EXAMPLE 177 by replacing
EXAMPLE 1F with EXAMPLE 180B. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.17 (s, 2H), 8.53-8.65 (m, 2H), 7.80 (d, 1H), 7.51 (d,
1H), 7.38-7.44 (m, 2H), 7.33 (d, 2H), 7.15 (s, 1H), 7.02-7.09 (m,
3H), 6.82-6.92 (m, 1H), 6.65 (d, 1H), 6.39 (s, 1H), 6.14 (s, 1H),
3.68-3.82 (m, 2H), 3.22-3.32 (m, 2H), 3.13-3.22 (m, 1H), 3.03 (s,
4H), 2.72 (s, 2H), 2.09-2.23 (m, 6H), 1.78-1.98 (m, 4H), 1.56-1.66
(m, 1H), 1.43-1.51 (m, 1H), 1.37 (t, 2H), 1.22-1.33 (m, 1H), 0.92
(s, 6H).
Example 181
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylme-
thyl]amino}phenyl)sulfonyl]benzamide
The title compound was prepared as in EXAMPLE 177 by replacing
EXAMPLE 1F with EXAMPLE 180C. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.17 (s, 2H), 8.53-8.65 (m, 2H), 7.80 (d, 1H), 7.51 (d,
1H), 7.38-7.44 (m, 2H), 7.33 (d, 2H), 7.15 (s, 1H), 7.02-7.09 (m,
3H), 6.82-6.92 (m, 1H), 6.65 (d, 1H), 6.39 (s, 1H), 6.14 (s, 1H),
3.68-3.82 (m, 2H), 3.22-3.32 (m, 2H), 3.13-3.22 (m, 1H), 3.03 (s,
4H), 2.72 (s, 2H), 2.09-2.23 (m, 6H), 1.78-1.98 (m, 4H), 1.56-1.66
(m, 1H), 1.43-1.51 (m, 1H), 1.37 (t, 2H), 1.22-1.33 (m, 1H), 0.92
(s, 6H).
Example 182
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-y-
lmethyl)amino]phenyl}sulfonyl)benzamide
The title compound was prepared as in EXAMPLE 177 by replacing
EXAMPLE 26C with EXAMPLE 150C. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.20 (br s, 1H), 11.17 (s, 1H), 8.63 (t, 1H), 8.59 (d,
1H), 7.79 (dd, 1H), 7.51 (d, 1H), 7.36 (m, 3H), 7.13 (m, 2H), 6.86
(dd, 1H), 6.66 (dd, 1H), 6.39 (s, 1H), 6.15 (d, 1H), 4.10 (s, 2H),
3.85 (m, 3H), 3.50 (m, 2H), 3.42 (m, 2H), 3.24 (m, 4H), 3.02 (m,
4H), 2.82 (m, 2H), 2.16 (m, 2H), 1.61 (m, 3H), 1.25 (m, 4H), 1.17
(s, 6H).
Example 183
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-indol-5-yloxy)benzamide
Example 183A
4-((4-hydroxy-1-methylpiperidin-4-yl)methylamino)-3-nitrobenzenesulfonamid-
e
This example was prepared by substituting
4-(aminomethyl)-1-methylpiperidin-4-ol for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 183B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 183A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.04 (s, 1H), 8.46-8.48 (m, 2H), 7.92 (s, 1H), 7.74 (d,
1H), 7.54 (d, 1H), 7.32-7.34 (m, 5H), 6.97-7.05 (m, 5H), 6.74-6.76
(m, 1H), 6.55-6.57 (m, 1H), 6.33 (s, 1H), 6.13 (d, 1H), 5.10 (s,
1H), 3.14-3.17 (m, 2H), 2.95 (br, 5H), 2.71 (br, 2H), 2.14-2.17 (m,
6H), 1.95 (br s, 2H), 1.70 (br, 4H), 1.36-1.39 (m, 2H), 1.24-1.26
(m, 2H), 0.92 (s, 6H).
Example 184
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide
Example 184A
ethyl 2-(1H-indol-5-yloxy)-3,4-difluorobenzoate
This example was prepared by substituting ethyl
2,3,4-trifluorobenzoate for ethyl 2,4-difluorobenzoate and
5-hydroxyindole for 5-hydroxyindazole in EXAMPLE 20A.
Example 184B
ethyl
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex--
1-enyl)methyl)piperazin-1-yl)-3-fluorobenzoate
This example was prepared by substituting EXAMPLE 184A for EXAMPLE
20A in EXAMPLE 20D.
Example 184C
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl-
)methyl)piperazin-1-yl)-3-fluorobenzoic acid
This example was prepared by substituting EXAMPLE 184B for EXAMPLE
1D in EXAMPLE 1E.
Example 184D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 184C for EXAMPLE
1E and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 10.98 (br s, 1H), 8.35 (d,
1H), 7.98 (dd, 1H), 7.59 (dd, 1H), 7.35 (m, 3H), 7.28 (t, 1H), 7.21
(d, 1H), 7.06 (d, 2H), 6.78 (m, 2H), 6.67 (m, 2H), 6.22 (s, 1H),
3.74 (dd, 2H), 3.39 (m, 4H), 3.06 (m, 3H), 2.97 (m, 4H), 2.79 (m,
2H), 2.73 (s, 3H), 2.29 (m, 2H), 2.18 (m, 2H), 2.05 (m, 2H), 1.81
(m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).
Example 185
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran--
4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 184C for EXAMPLE
1E and EXAMPLE 173C for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 10.98 (br s, 1H), 8.33 (d,
1H), 8.02 (dd, 1H), 7.50 (dd, 1H), 7.35 (m, 3H), 7.26 (t, 1H), 7.19
(d, 1H), 7.06 (d, 2H), 6.77 (dd, 2H), 6.67 (m, 2H), 6.22 (s, 1H),
3.90 (dd, 2H), 3.57 (m, 5H), 3.30 (dd, 2H), 3.06 (m, 3H), 2.94 (m,
4H), 2.78 (m, 2H), 2.27 (m, 4H), 2.18 (m, 2H), 1.98 (m, 4H), 1.80
(m, 2H), 1.55 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).
Example 186
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 183A for EXAMPLE
1F and EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.12 (s, 1H), 8.49 (s,
1H), 8.42 (s, 1H), 7.73-7.75 (m, 1H), 7.58 (d, 1H), 7.34 (d, 2H),
7.22 (s, 1H), 7.09 (d, 1H), 7.01-7.05 (m, 3H), 6.92 (t, 1H),
6.61-6.62 (m, 1H), 6.31 (d, 1H), 6.23 (s, 1H), 6.20 (s, 1H), 5.16
(s, 1H), 4.05 (s, 3H), 2.95 (br s, 6H), 2.71 (br s, 2H), 2.62 (br,
3H), 2.16 (br s, 6H), 1.95 (br s, 2H), 1.72 (br, 4H), 1.37-1.39 (m,
2H), 0.92 (s, 6H).
Example 187
N-[(4-{[(3S,4R)-1-benzyl-3-hydroxypiperidin-4-yl]amino}-3-nitrophenyl)sulf-
onyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-5-yloxy)benzamide
Example 187A
2-(1H-indol-5-yloxy)-N-(4-chloro-3-nitrophenylsulfonyl)-4-(4-((2-(4-chloro-
phenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide
This example was prepared by substituting
4-chloro-3-nitrobenzenesulfonamide for EXAMPLE 1F and EXAMPLE 26C
for EXAMPLE 1E in EXAMPLE 1G.
Example 187B
N-[(4-{[(3S,4R)-1-benzyl-3-hydroxypiperidin-4-yl]amino}-3-nitrophenyl)sulf-
onyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-5-yloxy)benzamide
A mixture of EXAMPLE 187A (0.158 g),
(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid (0.049
g), and triethylamine (0.1 mL) in dioxane (2 mL) was heated at
100.degree. C. overnight. The solvent was removed, and the residue
was re-dissolved in 1:1 methanol:dimethylsulfoxide (3 mL). It was
then purified by reverse phase Prep HPLC. The residue was purified
by reverse phase HPLC on a C18 column using a gradient of 20-80%
acetonitrile/0.1% TFA in water. The desired fractions were
collected, and the organic solvent was partially removed under
reduced pressure. The resulting mixture was treated with saturated
aqueous NaHCO.sub.3 mixture. It was then extracted with ethyl
acetate three times. The combined organic layers were washed with
brine, dried (MgSO.sub.4), filtered, and concentrated to give the
desired product. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.14 (s, 1H), 8.69 (d, 1H), 8.14 (d, 1H), 7.77 (dd, 1H),
7.51 (d, 1H), 7.29-7.41 (m, 9H), 7.10-7.13 (m, 1H), 7.13 (d, 2H),
6.84 (dd, 1H), 6.63 (dd, 1H), 6.38 (s, 1H), 6.13 (d, 1H), 5.21-5.22
(br s, 1H), 3.82 (m, 2H), 3.62 (br s, 2H), 3.01 (br s, 4H),
2.71-2.82 (m, 4H), 2.12-2.15 (m, 7H), 1.94 (br s, 2H), 1.81 (br s,
2H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).
Example 188
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfo-
nyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting
4-(aminomethyl)tetrahydro-2H-pyran-4-amine for
(3S,4R)-4-amino-1-benzylpiperidin-3-ol hydrochloric acid in EXAMPLE
187B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.08 (s, 1H), 8.60 (br s, 1H), 8.51 (d, 1H), 7.80 (dd, 1H), 7.54
(d, 1H), 7.32-7.36 (m, 4H), 7.12 (d, 1H), 7.03-7.05 (m, 3H), 6.77
(dd, 1H), 6.58 (dd, 1H), 6.35 (s, 1H), 6.13 (d, 1H), 3.61-3.70 (m,
4H), 3.53 (br s, 2H), 2.97 (br, 4H), 2.71 (br, 2H), 2.16 (br s,
6H), 1.94 (br s, 2H), 1.67-1.72 (m, 2H), 1.52-1.57 (m, 2H),
1.36-1.39 (m, 2H), 0.92 (s, 6H).
Example 189
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-
-3-nitrophenyl)sulfonyl]benzamide
Example 189A
4-[1-(2-methoxy-ethyl)-piperidin-4-ylamino]-3-nitro-benzenesulfonamide
1-(2-Methoxy-ethyl)-piperidin-4-ylamine (2.01 g) and triethylamine
(3.24 mL, 2.35 g) were added to 1,4-dioxane (60 mL).
4-Chloro-3-nitrobenzenesulfonamide (2.50 g) was added, and the
mixture was heated to 90.degree. C. for 16 hours. The mixture was
cooled and the material purified by flash column chromatography on
silica gel using 10% methanol in dichloromethane.
Example 189B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(l
1H-indol-5-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amin-
o}-3-nitrophenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 189A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.12 (br s, 1H), 8.52 (d,
1H), 8.18 (d, 1H), 7.76 (dd, 1H), 7.51 (d, 1H), 7.39-7.31 (m, 4H),
7.08-7.05 (m, 4H), 6.80 (dd, 1H), 6.61, (dd, 1H), 6.36 (t, 1H),
6.14 (d, 1H), 3.70 (m, 1H), 3.50 (t, 2H), 3.27 (s, 3H), 2.99 (m,
6H), 2.71 (br s, 4H), 2.16 (m, 6H), 2.02-1.90 (m, 6H), 1.65 (m,
2H), 1.37 (t, 2H), 0.92 (s, 6H).
Example 190
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 174A for EXAMPLE
1F and EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.21 (br s, 1H), 9.14 (s,
1H), 8.45 (d, 1H), 7.71 (dd, 1H), 7.52 (m, 2H), 7.34 (m, 2H), 7.26
(m, 1H), 7.15 (d, 1H), 7.04 (m, 2H), 6.95 (t, 1H), 6.67 (m, 1H),
6.38 (d, 1H), 6.25 (m, 2H), 3.01 (m, 4H), 2.87 (m, 5H), 2.72 (m,
2H), 2.33 (m, 4H), 2.15 (m, 6H), 1.95 (s, 2H), 1.39 (m, 2H), 0.92
(s, 6H).
Example 191
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfon-
yl]-2-(1H-indol-4-yloxy)benzamide
Example 191A
tert-butyl
4-(4-(N-(2-(1H-indol-4-yloxy)-4-(-4-((2-(4-chlorophenyl)-4,4-di-
methylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophen-
ylamino)piperidine-1-carboxylate
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 157A for EXAMPLE 1F in EXAMPLE 1G, except 5-7%
methanol in CH.sub.2Cl.sub.2 was used for the chromatography.
Example 191B
2-(1H-indol-4-yloxy)-N-(4-(1-(2-(tert-butyldimethylsilyloxy)ethyl)piperidi-
n-4-ylamino)-3-nitrophenylsulfonyl)-4-(-4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide
EXAMPLE 191A (400 mg) was dissolved in CH.sub.2Cl.sub.2 (2.5 mL)
and 4N HCl in dioxane (2.5 mL), then stirred at room temperature
for 30 minutes. The reaction was concentrated and then partitioned
between CH.sub.2Cl.sub.2 and saturated aqueous NaHCO.sub.3. The
organic layer was washed with brine and dried over
Na.sub.2SO.sub.4. After filtration and concentration the resultant
crude amine was slurried in CH.sub.2Cl.sub.2 (2.5 mL) and
(tert-butyldimethylsilyloxy)acetaldehyde (73 mg) was added. After
stirring for 15 minutes, sodium triacetoxyborohydride (400 mg) was
added and the reaction was stirred at room temperature overnight.
The reaction was diluted with CH.sub.2Cl.sub.2 and washed with
saturated aqueous NaHCO.sub.3 The organic layer was washed with
brine and dried over Na.sub.2SO.sub.4. The product was purified
using column chromatography using 1.0-2.5% methanol in
CH.sub.2Cl.sub.2
Example 191C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfon-
yl]-2-(1H-indol-4-yloxy)benzamide
EXAMPLE 191B (46 mg) was dissolved in tetrahydrofuran (0.8 mL),
then 1.0M tetrabutyl ammonium fluoride in 95/5
tetrahydrofuran/H.sub.2O (0.075 mL) was added and the reaction
stirred at room temperature overnight. The reaction was
concentrated and purified with column chromatography using 2-6%
methanol in CH.sub.2Cl.sub.2. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.15 (br s, 1H), 8.44 (d, 1H),
8.13 (br d, 1H), 7.74 (dd, 1H), 7.55 (d, 1H), 7.33 (d, 2H), 7.23
(s, 1H), 7.11 (d, 1H), 7.03 (m, 3H), 6.93 (dd, 1H), 6.64 (d, 1H),
6.33 (d, 1H), 6.23 (s, 1H), 6.22 (s, 1H), 3.75 (br s, 1H), 3.61 (br
s, 2H), 3.40 (br s, 2H), 3.10 (br s, 2H), 2.98 br s, 4H), 2.78 (br
s, 2H), 2.71 (s, 2H), 2.16 (br m, 6H), 2.00 (br d, 2H), 1.95 (s,
2H), 1.72 (br s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 194
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-
-3-nitrophenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 189A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.19 (br s, 1H), 8.46 (d,
1H), 8.17 (d, 1H), 7.72 (dd, 1H), 7.55 (d, 1H), 7.35 (d, 2H), 7.25
(t, 1H), 7.12 (d, 1H), 7.07-7.02 (m, 3H), 6.94 (t, 1H), 6.66, (dd,
1H), 6.36 (d, 1H), 6.24 (m, 2H), 3.73 (m, 1H), 3.52 (t, 2H), 3.27
(s, 3H), 3.00 (m, 6H), 2.79 (m, 2H), 2.72 (br s, 2H), 2.16 (m, 6H),
2.04-1.93 (m, 6H), 1.68 (m, 2H), 1.37 (t, 2H), 0.92 (s, 6H).
Example 195
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-indol-4-yloxy)benzamide
Example 195A
4-(1-(3-(tert-butyldimethylsilyloxy)propyl)piperidin-4-ylamino)-3-nitroben-
zenesulfonamide
A mixture of EXAMPLE 157B (300 mg),
(3-bromopropoxy)(tert-butyl)dimethylsilane (304 mg) and cesium
carbonate (967 mg) was suspended in anhydrous N,N-dimethylformamide
(5 mL). The reaction mixture was heated at 70.degree. C. overnight.
The reaction mixture was cooled to room temperature and diluted
with ethyl acetate. The organic phase was washed with water, brine,
dried over anhydrous sodium sulfate, and concentrated.
The crude material was purified using flash column purification
with 3-10% methanol/dichloromethane to afford the title
compound.
Example 195B
2-(1H-indol-4-yloxy)-N-(4-(1-(3-(tert-butyldimethylsilyloxy)propyl)piperid-
in-4-ylamino)-3-nitrophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 195A for EXAMPLE 1F in EXAMPLE 1G.
Example 195C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-indol-4-yloxy)benzamide
A mixture of EXAMPLE 195B (180 mg) in anhydrous tetrahydrofuran (1
mL) and tetrabutyl ammonium fluoride (0.5 mL 1M in tetrahydrofuran)
was stirred at room temperature for 2 hours. The solvent was
removed under vacuum. The residue was purified by reverse phase
HPLC on a C18 column using a gradient of 40-70% acetonitrile/0.1%
trifluroacetic acid in water to give the title compound as the
trifluoroacetate salt. The trifluroacetic acid salt was dissolved
in dichloromethane (6 ml) and washed with 50% aqueous NaHCO.sub.3.
The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concentrated to give the title compound. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.16 (s, 1H), 8.43
(d, 1H), 8.10 (m, 1H), 7.74 (dd, 1H), 7.57 (d, 1H), 7.34 (d, 2H),
7.23 (m, 1H), 7.10 (m, 1H), 7.02 (m, 3H), 6.93 (m, 1H), 6.65 (dd,
1H), 6.34 (d, 1H), 6.22 (m, 2H), 3.74 (m, 2H), 3.47 (m, 4H), 3.14
(m, 2H), 2.97 (m, 4H), 2.74 (m, 4H), 2.60 (m, 1H), 2.17 (m, 4H),
1.97 (m, 4H), 1.69 (m, 4H), 1.40 (m, 2H), 0.93 (s, 6H).
Example 196
4-[4-({4'-chloro-3-[3-(dimethylamino)propyl]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-yl-
methyl)amino]phenyl}sulfonyl)benzamide
Example 196A
4'-chloro-3-hydroxybiphenyl-2-carbaldehyde
The title compound was prepared as described in EXAMPLE 175A by
replacing 1-(2-bromophenyl)ethanone with
2-bromo-6-hydroxybenzaldehyde.
Example 196B
tert-butyl
4-((4'-chloro-3-hydroxybiphenyl-2-yl)methyl)piperazine-1-carbox-
ylate
The title compound was prepared as described in EXAMPLE 1A by
replacing 4'-chlorobiphenyl-2-carboxaldehyde with EXAMPLE 196A.
Example 196C
tert-butyl
4-((4'-chloro-3-(trifluoromethylsulfonyloxy)biphenyl-2-yl)methy-
l)piperazine-1-carboxylate
To a mixture of EXAMPLE 196B (390 mg) in pyridine (5 ml) at
0.degree. C. was added dropwise trifluoromethanesulfonic anhydride
(0.326 ml). The reaction mixture was stirred in an ice bath for 1
hour and diluted with ethyl acetate. The resulting mixture was
washed with brine extensively and the organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated to provide the title
compound.
Example 196D
tert-butyl
4-((4'-chloro-3-(3-(dimethylamino)prop-1-ynyl)biphenyl-2-yl)met-
hyl)piperazine-1-carboxylate
To a mixture of EXAMPLE 196C (380 mg),
N,N-dimethylprop-2-yn-1-amine (0.227 ml),
tetrakis(triphenylphosphine)palladium(0) (123 mg) and triethylamine
(0.492) in N,N-dimethylformamide (1.5 ml) was added copper(I)
iodide (27.1 mg) and .sup.tBuNI (394 mg). The reaction mixture was
heated at 100.degree. C. for 4 hours, cooled and diluted with ethyl
acetate. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated. The residue was purified by flash chromatography,
eluting with a mixture of methanol, dichloromethane and triethyl
amine to provide the title compound.
Example 196E
tert-butyl
4-((4'-chloro-3-(3-(dimethylamino)propyl)biphenyl-2-yl)methyl)p-
iperazine-1-carboxylate
Example 196D (200 mg) in methanol (8 ml) was treated with
platinum(IV) oxide (29.1 mg) under H.sub.2 atmosphere overnight.
The insoluble material was filtered off and the filtrate was
concentrated to provide the title compound.
Example 196F
3-(4'-chloro-2-(piperazin-1-ylmethyl)biphenyl-3-yl)-N,N-dimethylpropan-1-a-
mine
The title compound was prepared as described in EXAMPLE 175C by
replacing EXAMPLE 175B with EXAMPLE 196E.
Example 196G
ethyl
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-3-(3-(dimethylamino)propyl)bip-
henyl-2-yl)methyl)piperazin-1-yl)benzoate
The title compound was prepared as described in EXAMPLE 175D by
replacing EXAMPLE 175C with EXAMPLE 196F.
Example 196H
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-3-(3-(dimethylamino)propyl)biphenyl--
2-yl)methyl)piperazin-1-yl)benzoic acid
The title compound was prepared as described in EXAMPLE 175E by
replacing EXAMPLE 175D with EXAMPLE 196G.
Example 196I
4-[4-({4'-chloro-3-[3-(dimethylamino)propyl]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-yl-
methyl)amino]phenyl}sulfonyl)benzamide
The title compound was prepared as described in EXAMPLE 175F by
replacing EXAMPLE 175E with EXAMPLE 196H. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.11 (s, 1H), 8.38-8.44 (m,
2H), 7.68 (dd, 1H), 7.56 (d, 1H), 7.44 (d, 2H), 7.19-7.29 (m, 5H),
7.07 (d, 1H), 6.99 (dd, 1H), 6.87-6.93 (m, 2H), 6.59 (dd, 1H), 6.26
(d, 1H), 6.23 (s, 1H), 6.19 (d, 1H), 3.84 (dd, 2H), 3.22-3.29 (m,
4H), 2.87 (s, 6H), 2.69-2.75 (m, 2H), 2.59 (s, 5H), 2.14 (s, 4H),
1.83-1.92 (m, 3H), 1.56-1.65 (m, 2H), 1.19-1.31 (m, 4H), 0.81-0.90
(m, 1H)
Example 197
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-indol-5-yloxy)benzamide
Example 197A
2-(1H-indol-5-yloxy)-N-(4-(1-(3-(tert-butyldimethylsilyloxy)propyl)piperid-
in-4-ylamino)-3-nitrophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 195A for EXAMPLE 1F in EXAMPLE 1G.
Example 197B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 197A for EXAMPLE
195B in EXAMPLE 195C. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.07 (bs, 1H), 8.50 (d, 1H),
8.14 (d, 1H), 7.75 (dd, 1H), 7.52 (d, 1H), 7.34 (m, 4H), 7.02 (m,
4H), 6.78 (dd, 1H), 6.59 (dd, 1H), 6.34 (m, 1H), 6.14 (d, 1H), 3.46
(m, 4H), 3.16 (m, 2H), 2.98 (m, 4H), 2.68 (m, 4H), 2.60 (m, 1H),
2.16 (m, 6H), 1.97 (m, 4H), 1.68 (m, 4H), 1.38 (t, 2H), 0.93 (s,
6H).
Example 198
4-{4-[(4'-chloro-4-morpholin-4-yl-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl-
}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amin-
o]phenyl}sulfonyl)benzamide
Example 198A
tert-butyl
4-((4'-chloro-4-hydroxybiphenyl-2-yl)methyl)piperazine-1-carbox-
ylate
This example was prepared by substituting EXAMPLE 125A for
4'-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.
Example 198B
tert-butyl
4-((4'-chloro-4-(trifluoromethylsulfonyloxy)biphenyl-2-yl)methy-
l)piperazine-1-carboxylate
A mixture of EXAMPLE 198A (3.0 g), trifluoromethanesulfonic
anhydride (3.14 g) in anhydrous pyridine (50 mL) mixture was
stirred at room temperature overnight.
The reaction mixture was diluted with ethyl acetate. The organic
phase was washed with water, brine, dried over anhydrous sodium
sulfate and concentrated. The residue was used in the next step
without further purification.
Example 198C
tert-butyl
4-((4'-chloro-4-morpholinobiphenyl-2-yl)methyl)piperazine-1-car-
boxylate
A suspension of EXAMPLE 198B (500 mg), morpholine (80 mg),
palladium (II) acetate (22 mg), biphenyl-2-yldi-tert-butylphosphine
(50 mg) and cesium carbonate (427 mg) in anhydrous tetrahydrofuran
(6 mL) was heated at 50.degree. C. overnight. The reaction mixture
was cooled to room temperature and diluted with ethyl acetate. The
organic phase was washed with water, brine, dried over anhydrous
sodium sulfate, filtered and concentrated. The crude material was
purified by flash column purification with 30-50% ethyl
acetate/hexane to afford the title compound.
Example 198D
4-(4'-chloro-2-(piperazin-1-ylmethyl)biphenyl-4-yl)morpholine
This example was prepared by substituting EXAMPLE 198C for EXAMPLE
1A in EXAMPLE 1B.
Example 198E
methyl
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-4-morpholinobiphenyl-2-yl)met-
hyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 24F for EXAMPLE
20A and EXAMPLE 198D for EXAMPLE 20C in EXAMPLE 20D.
Example 198F
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-4-morpholinobiphenyl-2-yl)methyl)pip-
erazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 198E for EXAMPLE
1D in EXAMPLE 1E.
Example 198G
4-{4-[(4'-chloro-4-morpholin-4-yl-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl-
}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amin-
o]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 198F for EXAMPLE
26C in EXAMPLE 177. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.26 (bs, 1H), 8.63 (t, 1H),
8.49 (d, 1H), 7.66 (dd, 1H), 7.54 (d, 1H), 7.40 (m, 4H), 7.29 (m,
1H), 7.02 (m, 6H), 6.73 (dd, 1H), 6.39 (d, 1H), 6.30 (m, 2H), 3.85
(dd, 2H), 3.74 (m, 4H), 3.24 (m, 6H), 3.10 (m, 8H), 2.29 (m, 4H),
1.89 (m, 1H), 1.63 (m, 2H), 1.28 (m, 2H).
Example 199
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4--
ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide
Example 199A
tert-butyl
4-((4'-chloro-3-hydroxybiphenyl-2-yl)methyl)piperazine-1-carbox-
ylate
The title compound was prepared as described in EXAMPLE 1A by
replacing EXAMPLE 27C with EXAMPLE 196A.
Example 199B
tert-butyl
4-((4'-chloro-3-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)p-
iperazine-1-carboxylate
To a mixture of EXAMPLE 199A (1.5 g) in N,N-dimethylformamide (20
ml) was added 60% sodium hydride (0.596 g). The mixture was stirred
at room temperature for 30 minutes and dimethylaminoethyl chloride
hydrochloride salt (1.073 g) was added. After the resulting mixture
was stirred overnight, additional 60% sodium hydride (0.596 g) and
dimethylaminoethyl chloride hydrochloride salt (1.073 g) were
added. The reaction mixture was further stirred overnight, diluted
with ethyl acetate and washed with water, saturated NaHCO.sub.3 and
brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered,
and concentrated to provide the title compound.
Example 199C
2-(4'-chloro-2-(piperazin-1-ylmethyl)biphenyl-3-yloxy)-N,N-dimethylethanam-
ine
To a mixture of EXAMPLE 199B (2 g) in dichloromethane (10 ml) was
added trifluroacetic acid (10 ml) at 0.degree. C. The reaction
mixture was stirred at room temperature for 30 minutes and
concentrated. The residue was loaded onto a C18 column, and eluted
with 0-50% 0.1% trifluroacetic acid/water in acetonitrile. The
title compound was obtained as a trifluroacetic acid salt.
Example 199D
ethyl
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)bip-
henyl-2-yl)methyl)piperazin-1-yl)benzoate
The title compound was prepared as described in EXAMPLE 175D by
replacing EXAMPLE 175C with EXAMPLE 199C.
Example 199E
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-3-(2-(dimethylamino)ethoxy)biphenyl--
2-yl)methyl)piperazin-1-yl)benzoic acid
The title compound was prepared as described in EXAMPLE 175E by
replacing EXAMPLE 175D with EXAMPLE 199D.
Example 199F
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4--
ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide
The title compound was prepared as described in EXAMPLE 175F by
replacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 199E and EXAMPLE
173C, respectively. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.13 (s, 1H), 8.41 (d, 1H),
8.12 (d, 1H), 7.70 (dd, 1H), 7.58 (d, 1H), 7.52 (d, 2H), 7.43 (d,
2H), 7.31 (t, 1H), 7.22 (t, 1H), 7.06 (dd, 2H), 6.89-6.97 (m, 2H),
6.84 (d, 1H), 6.64 (dd, 1H), 6.30 (d, 1H), 6.24 (dd, 2H), 4.14 (t,
2H), 3.90 (dd, 2H), 3.53-3.73 (m, 2H), 3.22-3.32 (m, 4H), 2.93 (s,
6H), 2.34-2.46 (m, 7H), 2.29 (s, 5H), 1.97 (d, 2H), 1.73 (d, 2H),
1.41-1.62 (m, 4H).
Example 201
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2--
(1H-indol-5-yloxy)benzamide
Example 201A
4-(4-(diethylamino)cyclohexylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting
N.sup.1,N.sup.1-diethylcyclohexane-1,4-diamine for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A.
Example 201B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2--
(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 201A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (500
MHz, pyridine-d.sub.5) 6 ppm 12.28 (s, 1H), 9.29 (d, 1H), 8.29-8.38
(m, 2H), 8.19 (d, 1H), 7.52-7.57 (m, 2H), 7.40-7.47 (m, 3H), 7.10
(dd, 1H), 7.06 (d, 2H), 6.92 (d, 1H), 6.74 (dd, 1H), 6.61 (s, 1H),
6.55 (d, 1H), 3.31-3.42 (m, 1H), 3.00-3.08 (m, 4H), 2.76 (s, 2H),
2.54-2.61 (m, 1H), 2.51 (q, 4H), 2.21-2.28 (m, 2H), 2.08-2.15 (m,
4H), 2.04 (d, 2H), 1.97 (s, 2H), 1.81 (d, 2H), 1.38 (t, 2H),
1.29-1.36 (m, 2H), 1.17-1.28 (m, 2H), 1.05 (t, 6H), 0.93 (s,
6H).
Example 202
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-indol-4-yloxy)benzamide
Example 202A
4-(4-(dimethylamino)cyclohexylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting
N.sup.1,N.sup.1-dimethylcyclohexane-1,4-diamine for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A.
Example 202B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 202A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (500
MHz, pyridine-d.sub.5) 6 ppm 12.45 (s, 1H), 9.21 (d, 1H), 8.33 (d,
1H), 8.27 (dd, 1H), 8.18 (d, 1H), 7.48 (t, 1H), 7.45 (d, 2H), 7.40
(d, 1H), 7.11 (t, 1H), 7.08 (d, 2H), 6.87 (d, 1H), 6.72-6.81 (m,
3H), 6.67 (d, 1H), 3.31-3.41 (m, 1H), 3.00-3.06 (m, 4H), 2.77 (s,
2H), 2.31 (s, 6H), 2.25 (t, 2H), 2.20-2.25 (m, 1H), 2.10-2.16 (m,
4H), 2.00-2.07 (d, 2H), 1.97 (s, 2H), 1.88 (d, 2H), 1.39 (t, 3H),
1.34 (d, 2H), 1.15-1.28 (m, 4H), 0.94 (s, 6H).
Example 203
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2--
(1H-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 201A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (500
MHz, pyridine-d.sub.5) .delta. 12.44 (s, 1H), 9.21 (d, 1H), 8.34
(d, 1H), 8.28 (dd, 1H), 8.18 (d, 1H), 7.47-7.50 (m, 1H), 7.45 (d,
2H), 7.40 (d, 1H), 7.11 (t, 1H), 7.08 (d, 2H), 6.90 (d, 1H),
6.73-6.81 (m, 3H), 6.67 (d, 1H), 3.32-3.40 (m, 1H), 2.99-3.06 (m,
4H), 2.76 (s, 2H), 2.52-2.60 (m, 1H), 2.49 (q, 4H), 2.25 (t, 2H),
2.09-2.16 (m, 4H), 2.04 (d, 2H), 1.97 (s, 2H), 1.79 (d, 2H),
1.29-1.42 (m, 4H), 1.16-1.28 (m, 2H), 1.04 (t, 6H), 0.92-0.95 (m,
6H).
Example 204
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-
-3-nitrophenyl}sulfonyl)benzamide
Example 204A
trans-4-(4-morpholinocyclohexylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting
trans-4-morpholinocyclohexanamine for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A.
Example 204B
trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-
-3-nitrophenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 204A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (500
MHz, pyridine-d.sub.5) .delta. 12.45 (s, 1H), 9.21 (d, 1H), 8.36
(d, 1H), 8.26 (dd, 1H), 8.16 (d, 1H), 7.47-7.51 (m, 1H), 7.45 (d,
1H), 7.40 (d, 1H), 7.12 (t, 1H), 6.87 (d, 1H), 6.73-6.81 (m, 3H),
6.68 (d, 1H), 3.71-3.78 (m, 2H), 3.33-3.42 (m, 1H), 3.00-3.06 (m,
4H), 2.76 (s, 2H), 2.44-2.52 (m, 4H), 2.25 (t, 2H), 2.16-2.23 (m,
2H), 2.09-2.16 (m, 4H), 2.06 (d, 2H), 1.97 (s, 2H), 1.86 (s, 2H),
1.39 (t, 2H), 1.17-1.35 (m, 6H), 0.94 (s, 6H).
Example 205
4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide
The title compound was prepared as described in EXAMPLE 177 by
replacing EXAMPLE 26C and EXAMPLE 1F with EXAMPLE 199E and EXAMPLE
21A, respectively. .sup.1H NMR (500 MHz, dichloromethane-d.sub.2)
.delta. 8.70 (d, 1H), 8.56 (s, 1H), 8.40 (d, 1H), 7.95 (dd, 1H),
7.91 (d, 1H), 7.46 (d, 2H), 7.24-7.35 (m, 5H), 7.15 (t, 1H), 6.90
(dd, 2H), 6.83 (d, 1H), 6.75 (d, 1H), 6.60 (dd, 1H), 6.41 (d, 1H),
6.19 (d, 1H), 4.05 (t, 2H), 3.58 (s, 1H), 3.32 (s, 2H), 2.95-3.02
(m, 4H), 2.66-2.80 (m, 4H), 2.30-2.35 (m, 4H), 2.24-2.29 (m, 9H),
2.15-2.23 (m, 2H), 2.05 (d, 2H), 1.63-1.73 (m, 2H)
Example 206
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4--
yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzam-
ide
The title compound was prepared as described in EXAMPLE 177 by
replacing EXAMPLE 26C and EXAMPLE 1F with EXAMPLE 175E and EXAMPLE
21A, respectively. .sup.1H NMR (400 MHz, dichloromethane-d.sub.2)
.delta. 8.70 (d, 1H), 8.51 (s, 1H), 8.40 (d, 1H), 7.94 (dd, 1H),
7.90 (d, 1H), 7.54 (d, 1H), 7.33 (t, 4H), 7.21-7.27 (m, 2H),
7.10-7.19 (m, 4H), 6.91 (d, 1H), 6.73 (d, 1H), 6.55-6.60 (m, 1H),
6.41 (s, 1H), 6.16 (d, 1H), 3.52-3.63 (m, 1H), 3.36 (q, 1H),
2.96-3.07 (m, 4H), 2.72-2.79 (m, 2H), 2.33-2.41 (m, 2H), 2.27 (s,
3H), 2.14-2.27 (m, 4H), 2.00-2.09 (m, 2H), 1.63-1.74 (m, 2H), 1.19
(d, 3H).
Example 207
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(({[4-(dimethylamino)tetrahydro-2H-pyran-4-yl]methyl}amino)-3--
nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting
4-(aminomethyl)-N,N-dimethyltetrahydro-2H-pyran-4-amine for
(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in
EXAMPLE 187B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.17 (s, 1H), 8.84 (br s, 1H), 8.59 (d, 1H), 7.84 (dd,
1H), 7.51 (d, 1H), 7.39-7.43 (m, 2H), 7.33 (d, 2H), 7.17-7.21 (m,
2H), 7.03 (d, 2H), 6.89 (dd, Hz, 1H), 6.64 (d, 1H), 6.40 (s, 1H),
6.13 (d, 1H), 3.72-3.75 (m, 2H), 3.34-3.57 (m, 4H), 3.02 (br, 4H),
2.71 (br, 2H), 2.27 (s, 6H), 2.16 (br s, 6H), 1.94 (br s, 2H),
1.78-1.85 (m, 2H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).
Example 208
N-({4-[(2-aminocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlor-
ophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-
-5-yloxy)benzamide
Example 208A
This example was prepared by substituting tert-butyl
2-aminocyclohexylcarbamate for
(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in
EXAMPLE 187B.
Example 208B
N-({4-[(2-aminocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlor-
ophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-
-5-yloxy)benzamide
EXAMPLE 208A (0.1 g) in dimethylsulfoxide (4 mL) was heated under
microwave conditions (200.degree. C., 1 hour). The residue was
purified by reverse phase HPLC on a C18 column using a gradient of
30-70% acetonitrile/0.1% TFA in water. The desired fractions were
collected, and the organic solvent was partially removed under
reduced pressure. The resulting mixture was treated with saturated
aqueous NaHCO.sub.3 mixture. It was then extracted with ethyl
acetate three times. The combined organic layers were washed with
brine, dried (MgSO.sub.4), filtered, and concentrated to give the
title compound. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.02 (s, 1H), 8.45 (s, 1H), 8.05 (d, 1H), 7.79-7.81 (m,
1H), 7.56 (d, 1H), 7.30-7.34 (m, 4H), 6.98-7.06 (m, 4H), 6.73 (d,
1H), 6.54 (dd, 1H), 6.33 (s, 1H), 6.11 (d, 1H), 3.64-3.70 (m, 1H),
2.93 (br, 4H), 2.71 (br, 2H), 2.14-2.16 (br s, 6H), 1.95 (br s,
2H), 1.67-1.73 (m, 2H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).
Example 209
4-[4-({4'-chloro-4-[3-(dimethylamino)prop-1-ynyl]-1,1'-biphenyl-2-yl}methy-
l)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
Example 209A
tert-butyl
4-((4'-chloro-4-(3-(dimethylamino)prop-1-ynyl)biphenyl-2-yl)met-
hyl)piperazine-1-carboxylate
A suspension of EXAMPLE 198B (800 mg),
N,N-dimethylprop-2-yn-1-amine (373 mg), copper(I) iodide (57 mg),
tetrakis(triphenylphosphine)palladium(O) (259 mg), triethylamine
(757 mg) and tert-butyl ammonium iodide (829 mg) in anhydrous
N,N-dimethylformamide (5 mL) was heated at 100.degree. C. for 5
hours. The reaction mixture was cooled to room temperature and
diluted with ethyl acetate. The organic phase was washed with
water, brine, dried over anhydrous sodium sulfate, filtered, and
concentrated. The crude material was purified by flash column
purification with 0-3% methanol/dichloromethane to afford the title
compound.
Example 209B
3-(4'-chloro-2-(piperazin-1-ylmethyl)biphenyl-4-yl)-N,N-dimethylprop-2-yn--
1-amine
This example was prepared by substituting EXAMPLE 209A for EXAMPLE
1A in EXAMPLE 1B.
Example 209C
methyl
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-4-(3-(dimethylamino)prop-1-yn-
yl)biphenyl-2-yl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 24F for EXAMPLE
20A and EXAMPLE 209B for EXAMPLE 20C in EXAMPLE 20D.
Example 209D
2-(1H-indol-4-yloxy)-4-(4-((4'-chloro-4-(3-(dimethylamino)prop-1-ynyl)biph-
enyl-2-yl)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 209C for EXAMPLE
1D in EXAMPLE 1E.
Example 209E
4-[4-({4'-chloro-4-[3-(dimethylamino)prop-1-ynyl]-1,1'-biphenyl-2-yl}methy-
l)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 209D for EXAMPLE
26C in EXAMPLE 177. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.23 (bs, 1H), 8.57 (t, 1H),
8.47 (d, 1H), 7.67 (dd, 1H), 7.54 (m, 2H), 7.43 (m, 5H), 7.24 (m,
2H), 7.14 (m, 1H), 7.03 (m, 1H), 6.94 (m, 1H), 6.71 (d, 1H), 6.38
(d, 1H), 6.27 (d, 2H), 3.85 (m, 2H), 3.60 (m, 2H), 3.23 (m, 6H),
3.04 (m, 4H), 2.35 (s, 6H), 2.28 (m, 4H), 1.88 (m, 1H), 1.58 (m,
2H), 1.24 (m, 2H).
Example 210
4-(4-({[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperi-
din-4-yl]amino}phenyl)sulfonyl]benzamide
Example 210A
3-nitro-4-(1-(4,4,4-trifluorobutyl)piperidin-4-ylamino)benzenesulfonamide
EXAMPLE 157B (600 mg) was combined with
1,1,1-trifluoro-4-iodobutane (595 mg) and potassium carbonate (829
mg) in acetonitrile (15 mL). The reaction was heated to 70.degree.
C. overnight. The reaction was concentrated, and then taken up in
ether and concentrated again. The product was used in the next step
without further purification.
Example 210B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperid-
in-4-yl]amino}phenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 210A for EXAMPLE
1F and EXAMPLE 55B for EXAMPLE 1E in EXAMPLE 1G. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.20 (s, 1H), 8.47 (d,
1H), 8.20 (d, 1H), 7.72 (dd, 1H), 7.54 (d, 1H), 7.34 (d, 2H), 7.25
(t, 1H), 7.14 (d, 1H), 7.05 (m, 3H), 6.95 (t, 1H), 6.68 (dd, 1H),
6.38 (d, 1H), 6.25 (s, 2H), 3.71 (m, 1H), 3.01 (m, 4H), 2.92 (m,
2H), 2.72 (s, 2H), 2.40 (m, 2H), 2.30 (m, 2H), 2.16 (m, 6H), 1.95
(m, 4H), 1.68 (m, 4H), 1.38 (t, 2H), 1.24 (br s, 1H), 0.92 (s,
6H).
Example 211
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[2-(4-hydroxy-1-methylpiperidin-4-yl)ethyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting
4-(2-aminoethyl)-1-methylpiperidin-4-ol for
(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in
EXAMPLE 187B. 1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.05 (s, 1H), 8.61 (s, 1H), 8.47 (d, 1H), 7.77 (dd, 1H), 7.54 (d,
1H), 7.32-7.34 (m, 4H), 7.04 (d, 2H), 7.01 (s, 1H), 6.90 (d, 2H),
6.76 (dd, 1H), 6.57 (dd, 1H), 6.33 (s, 1H), 6.13 (d, 1H), 4.92 (s,
1H), 3.43-3.46 (m, 2H), 2.95-3.01 (br, 8H), 2.71 (br, 2H), 2.65 (s,
3H), 2.12-2.16 (br s, 6H), 1.95 (br s, 2H), 1.77-1.80 (m, 2H),
1.67-1.71 (m, 4H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).
Example 212
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-yl)piperidin-4-
-yl]amino}phenyl)sulfonyl]benzamide
This example was prepared by substituting
4-(2-aminoethyl)-1-methylpiperidin-4-ol for
(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in
EXAMPLE 187B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.16 (s, 1H), 8.58 (s, 1H), 8.28 (d, 1H), 7.82 (dd, 1H),
7.51 (d, 1H), 7.39-7.42 (m, 2H), 7.33 (d, 2H), 7.20 (d, 1H), 7.17
(d, 1H), 7.14 (d, 1H), 7.03 (d, 2H), 6.86 (d, 1H), 6.85 (d, 1H),
6.65 (dd, 1H), 6.39 (s, 1H), 6.15 (d, 1H), 3.87-3.90 (m, 2H),
3.20-3.24 (m, 2H), 3.04 (br, 4H), 2.73 (br, 2H), 2.11-2.17 (m, 5H),
1.95 (br s, 2H), 1.71-1.75 (m, 2H), 1.36-1.39 (m, 2H), 0.92 (s,
6H).
Example 213
4-(4-{[4'-chloro-4-(2-hydroxyethoxy)-1,1'-biphenyl-2-yl]methyl}piperazin-1-
-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)a-
mino]phenyl}sulfonyl)benzamide
Example 213A
4-(2-(tert-butyldimethylsilyloxy)ethoxy)-4'-chlorobiphenyl-2-carbaldehyde
A mixture of EXAMPLE 125A (0.5 g),
(2-bromoethoxy)(tert-butyl)dimethylsilane (0.771 g) and cesium
carbonate (1.4 g) was suspended in anhydrous N,N-dimethylformamide
(5 mL). The reaction mixture was heated at 70.degree. C. overnight.
The reaction mixture was cooled to room temperature and diluted
with ethyl acetate. The organic phase was washed with water, brine,
dried over anhydrous sodium sulfate, filtered, and concentrated.
The crude material was purified by flash column purification with
0-5% ethyl acetate/hexane to afford the title compound.
Example 213B
methyl
2-(1H-indol-4-yloxy)-4-(4-((4-(2-(tert-butyldimethylsilyloxy)ethoxy-
)-4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate
This example was made by substituting EXAMPLE 213A for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 213C
2-(1H-indol-4-yloxy)-4-(4-((4-(2-(tert-butyldimethylsilyloxy)ethoxy)-4'-ch-
lorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 213B for EXAMPLE
1D in EXAMPLE 1E.
Example 213D
2-(1H-indol-4-yloxy)-4-(4-((4-(2-(tert-butyldimethylsilyloxy)ethoxy)-4'-ch-
lorobiphenyl-2-yl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyra-
n-4-yl)methylamino)phenylsulfonyl)benzamide
This example was prepared by substituting EXAMPLE 213C for EXAMPLE
1E in EXAMPLE 1G.
Example 213E
4-(4-{[4'-chloro-4-(2-hydroxyethoxy)-1,1'-biphenyl-2-yl]methyl}piperazin-1-
-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)a-
mino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 213D for EXAMPLE
195B in EXAMPLE 195C. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.24 (m, 1H), 8.62 (t, 1H),
8.50 (d, 1H), 7.67 (dd, 1H), 7.54 (m, 1H), 7.43 (d, 2H), 7.37 (d.
2H). 7.28 (m, 1H), 7.15 (m, 2H), 7.05 (m, 2H), 6.96 (m, 1H), 6.90
(dd, 1H), 6.73 (dd, 1H), 6.40 (d, 1H), 6.31 (m, 1H), 6.27 (m, 1H),
4.82 (t, 1H), 3.99 (t, 2H), 3.86 (m, 2H), 3.71 (m, 2H), 3.26 (m,
6H), 2.66 (m, 2H), 2.31 (m, 5H), 1.89 (m, 1H), 1.63 (m, 2H), 1.27
(m, 2H).
Example 214
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-indol-5-yloxy)benzamide
Example 214A
tert-butyl 1-(cyclopropylmethyl)piperidin-4-ylcarbamate
This example was prepared by substituting cyclopropanecarbaldehyde
for 4'-chlorobiphenyl-2-carboxaldehyde and tert-butyl
piperidin-4-ylcarbamate for tert-butyl piperazine-1-carboxylate in
EXAMPLE 1A.
Example 214B
1-(cyclopropylmethyl)piperidin-4-amine
bis(2,2,2-trifluoroacetate)
This example was prepared by substituting EXAMPLE 214A for EXAMPLE
1A in EXAMPLE 1B.
Example 214C
4-(1-(cyclopropylmethyl)piperidin-4-ylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting EXAMPLE 214B for
1-(2-Methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A.
Example 214D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 214C for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (500
MHz, pyridine-d.sub.5) .delta. 12.28 (s, 1H), 9.30 (d, 1H), 8.49
(d, 1H), 8.34 (dd, 1H), 8.18 (d, 1H), 7.52-7.56 (m, 2H), 7.41-7.46
(m, 3H), 7.09 (dd, 1H), 7.06 (d, 2H), 6.91 (d, 1H), 6.73 (dd, 1H),
6.61 (d, 1H), 6.54 (d, 1H), 3.45-3.56 (m, 1H), 3.00-3.08 (m, 4H),
2.87 (d, 2H), 2.76 (s, 2H), 2.25 (t, 2H), 2.19 (d, 4H), 2.09-2.14
(m, 4H), 1.97 (s, 4H), 1.63-1.73 (m, 2H), 1.38 (t, 2H), 0.84-0.91
(m, 1H), 0.43-0.50 (m, 2H), 0.11 (q, H).
Example 215
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trifl-
uoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
Example 215A
4-(4-methylpiperazin-1-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonam-
ide
This example was prepared by substituting 4-methylpiperazin-1-amine
for (tetrahydropyran-4-yl)methanamine and EXAMPLE 159C for
4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 1F.
Example 215B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trifl-
uoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 215A for EXAMPLE
1F and EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.21 (br s, 1H), 8.09 (m,
1H), 7.98 (m, 1H), 7.83 (dd, 1H), 7.53 (d, 1H), 7.45 (d, 1H), 7.34
(d, 2H), 7.26 (t, 1H), 7.16 (d, 1H), 7.04 (d, 2H), 6.97 (t, 1H),
6.66 (dd, 1H), 6.39 (d, 1H), 6.24 (m, 2H), 2.87 (m, 13H), 2.38 (s,
3H), 2.17 (m, 6H), 1.95 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H)
Example 216
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperid-
in-4-yl]amino}phenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 210A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.13 (s, 1H), 10.89 (br s,
1H), 8.55 (d, 1H), 8.22 (d, 1H), 7.79 (dd, 1H), 7.50 (d, 1H), 7.34
(m, 4H), 7.07 (m, 4H), 6.83 (dd, 1H), 6.63 (dd, 1H), 6.37 (m, 1H),
6.15 (d, 1H), 3.71 (m, 1H), 3.01 (m, 4H), 2.92 (m, 2H), 2.72 (s,
2H), 2.40 (m, 2H), 2.30 (m, 2H), 2.16 (m, 6H), 1.95 (m, 4H), 1.68
(m, 4H), 1.38 (t, 2H), 1.24 (br s, 1H), 0.92 (s, 6H).
Example 217
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4--
yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzam-
ide
The title compound was prepared as described in EXAMPLE 177 by
replacing EXAMPLE 26C and EXAMPLE 1F with EXAMPLE 175E and EXAMPLE
174A, respectively. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.21 (s, 1H), 9.15 (s, 1H),
8.45 (d, 1H), 7.70 (dd, 1H), 7.43-7.56 (m, 5H), 7.34-7.41 (m, 1H),
7.24-7.31 (m, 4H), 7.10-7.16 (m, 2H), 6.94 (t, 1H), 6.66 (dd, 1H),
6.37 (d, 1H), 6.24 (dd, 2H), 2.80-3.02 (m, 10H), 2.28-2.39 (m, 5H),
2.14-2.24 (m, 2H), 1.16 (d, 3H).
Example 218
4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydrox-
ymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-y-
l)amino]-3-nitrophenyl}sulfonyl)benzamide
Example 218A
2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde
This example was prepared by substituting EXAMPLE 18C for EXAMPLE
143C in EXAMPLE 143D.
Example 218B
tert-butyl
4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)-3-(h-
ydroxymethyl)piperazine-1-carboxylate
This example was prepared by substituting EXAMPLE 218A for EXAMPLE
27C and tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate for
tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
Example 218C
(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-2-yl)-
methanol
This example was prepared by substituting EXAMPLE 218B for EXAMPLE
1A in EXAMPLE 1B.
Example 218D
ethyl
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex--
1-enyl)methyl)-3-(hydroxymethyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 218C for EXAMPLE
20C and EXAMPLE 26A for EXAMPLE 20A in EXAMPLE 20D.
Example 218E
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl-
)methyl)-3-(hydroxymethyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 218D for EXAMPLE
1D in EXAMPLE 1E.
Example 218F
4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydrox-
ymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-y-
l)amino]-3-nitrophenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 218E for EXAMPLE
26C and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.07 (s, 1H), 8.50 (d,
1H), 8.14 (d, 1H), 7.45 (d, J=9.46 Hz, 1H), 7.52 (d, 1H), 7.32-7.35
(m, 4H), 6.99-7.05 (m, 4H), 6.78 (dd, 1H), 6.58-6.59 (m, 1H), 6.34
(s, 1H), 6.14 (d, 1H), 4.42-4.44 (m, 1H), 3.72 (br s, 1H),
3.10-3.25 (m, 6H), 3.00 (br, 2H), 2.58-2.69 (m, 6H), 1.82-2.01 (m,
6H), 1.70 (br, 2H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).
Example 219
4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydrox-
ymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro--
2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 218E for EXAMPLE
26C and EXAMPLE 173C for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.11 (s, 1H), 8.52
(d, 1H), 8.20 (d, 1H), 7.77 (dd, 1H), 7.52 (d, 1H), 7.32-7.38 (m,
4H), 7.03-7.07 (m, 4H), 6.81 (dd, 1H), 6.58-6.60 (m, 1H), 6.36 (s,
1H), 6.14 (d, 1H), 4.44 (s, 1H), 3.92 (dd, 2H), 3.71 (br s, 1H),
3.41-3.43 (m, 2H), 3.02-3.06 (m, 4H), 2.55-2.72 (m, 6H), 2.18-2.24
(m, 2H), 1.91-2.00 (m, 8H), 1.76-1.80 (m, 2H), 1.63-1.65 (m, 2H),
1.49-1.51 (m, 2H), 1.35-1.38 (m, 2H), 0.92 (s, 6H).
Example 220
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trifl-
uoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 215A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.14 (s, 1H), 8.15 (d, 1H), 8.04 (s, 1H), 7.95 (dd, 1H),
7.50 (t, 2H), 7.35 (m, 4H), 7.12 (d, 1H), 7.04 (d, 2H), 6.83 (dd,
1H), 6.61 (dd, 1H), 6.39 (m, 1H), 6.12 (d, 1H), 2.92 (m, 10H), 2.71
(s, 2H), 2.35 (s, 3H), 2.17 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H),
0.92 (s, 6H).
Example 221
4-(4-{[4'-chloro-4-(2-hydroxyethoxy)-1,1'-biphenyl-2-yl]methyl}piperazin-1-
-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide
Example 221A
2-(H-indol-4-yloxy)-4-(4-((4-(2-(tert-butyldimethylsilyloxy)ethoxy)-4'-chl-
orobiphenyl-2-yl)methyl)piperazin-1-yl)-N-(4-(1-methylpiperidin-4-ylamino)-
-3-nitrophenylsulfonyl)benzamide
This example was prepared by substituting EXAMPLE 213C for EXAMPLE
1E and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G.
Example 221B
4-(4-{[4'-chloro-4-(2-hydroxyethoxy)-1,1'-biphenyl-2-yl]methyl}piperazin-1-
-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 221A for EXAMPLE
195B in EXAMPLE 195. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) S 11.12 (s, 1H), 8.42 (d, 1H), 8.10 (d,
1H), 7.74 (dd, 1H), 7.58 (d, 1H), 7.40 (m, 4H), 7.21 (m, 1H), 7.06
(m, 4H), 6.90 (m, 2H), 6.65 (m, 1H), 6.31 (d, 1H), 6.23 (m. 2H),
4.84 (t. 1H), 4.00 (t, 2H), 3.71 (m, 3H), 3.24 (m, 4H), 3.02 (m,
6H), 2.66 (m, 2H), 2.32 (m, 5H), 2.00 (m, 2H), 1.69 (m, 2H).
Example 222
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]a-
mino}phenyl)sulfonyl]benzamide
Example 222A
3-nitro-4-[3-(3-oxo-piperazin-1-yl)-propylamino]-benzenesulfonamide
4-(3-Amino-propyl)-piperazin-2-one (3.45 g) and triethylamine (5.18
mL, 3.76 g) were added to 1,4-dioxane (100 mL) and
N,N-dimethylacetamide (20 mL) and mixed until dissolved.
4-Chloro-3-nitrobenzenesulfonamide (4.00 g) was added, and the
mixture was heated to 90.degree. C. for 16 hours. The mixture was
cooled and the solvent was removed under vacuum. The material
purified by recrystallization from 20% methanol in dichloromethane
with subsequent washing of the recrystallized solid with 10%
methanol in dichloromethane followed by washing with 100%
dichloromethane.
Example 222B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]a-
mino}phenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 222A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.16 (br s, 1H), 8.85 (t,
1H), 8.58 (d, 1H), 7.79 (dd, 1H), 7.74 (br s, 1H), 7.51 (d, 1H),
7.43-7.37 (m, 2H), 7.34 (d, 2H), 7.16 (d, 1H), 7.07-7.01 (m, 3H),
6.86 (dd, 1H), 6.65, (d, 1H), 6.39 (t, 1H), 6.15 (d, 1H), 3.43 (q,
2H), 3.17 (t, 2H), 3.03 (m, 4H), 2.95 (s, 2H), 2.72 (s, 2H), 2.56
(t, 2H), 2.47 (t, 2H), 2.16 (m, 6H), 1.95 (br s, 2H), 1.79 (m, 2H),
1.38 (t, 2H), 0.92 (s, 6H).
Example 223
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]a-
mino}phenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 222A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) 11.24 (br s, 1H), 8.83 (t, 1H),
8.50 (d, 1H), 7.75 (br s, 1H), 7.68 (dd, 1H), 7.53 (d, 1H), 7.34
(d, 2H), 7.28 (t, 1H), 7.18 (d, 1H), 7.04 (d, 2H), 7.02-6.94 (m,
2H), 6.71 (dd, 1H), 6.42 (d, 1H), 6.29-6.23 (m, 2H), 3.43 (q, 2H),
3.17 (m, 2H), 3.05 (m, 4H), 2.96 (s, 2H), 2.72 (s, 2H), 2.57 (t,
2H), 2.48 (t, 2H), 2.17 (m, 6H), 1.95 (br s, 2H), 1.79 (m, 2H),
1.38 (t, 2H), 0.92 (s, 6H).
Example 224
4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-y-
l)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitropheny-
l}sulfonyl)benzamide
Example 224A
2-chloro-5-hydroxycyclohex-1-enecarbaldehyde
Phosphorus oxychloride (4.08 mL) was added to cooled (-10.degree.
C.) N,N-dimethylformamide (20 mL). The temperature was maintained
below 0.degree. C. Stirring was continued for another 30 minutes
before the addition of 4-(tert-butyldimethylsilyloxy)cyclohexanone
(10 g). The mixture was then stirred at room temperature for 2
hours before it was diluted with ethyl acetate (300 mL) and washed
with water (3.times.), brine and dried over Na.sub.2SO.sub.4. After
filtration and concentration, the crude product was used directly
in the next reaction without further purification.
Example 224B
2-(4-chlorophenyl)-5-hydroxycyclohex-1-enecarbaldehyde
To a mixture of 4-chlorophenylboronic acid (6.88 g), EXAMPLE 224A
(4.65 g), palladium(II) acetate (131 mg), K.sub.2CO.sub.3 (18.24 g)
and tetrabutylammonium bromide (14.18 g) was added water (200 mL).
The mixture was stirred at 50.degree. C. for 4 hours, cooled, and
diluted with ethyl acetate (400 mL) and washed with water
(3.times.) and brine and dried over Na.sub.2SO.sub.4. After
filtration and concentration, the residue was loaded on a column
and eluted with 5-20% ethyl acetate in hexane to give the title
compound.
Example 224C
methyl
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5-hydroxycyclohex-1--
enyl)methyl)piperazin-1-yl)benzoate
To a mixture of EXAMPLE 224B (0.8 g) and EXAMPLE 150A (1.2 g) in
dichloromethane (20 mL) was added sodium triacetoxyborohydride (1.2
g). The mixture was stirred overnight. The mixture was diluted with
ethyl acetate (200 mL) and washed with 2% NaOH, water and brine.
After drying over Na.sub.2SO.sub.4, the solvent was evaporated
under vacuum and the residue was loaded on a column and eluted with
5-10% methanol in dichloromethane to give the title compound.
Example 224D
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5-hydroxycyclohex-1-enyl)me-
thyl)piperazin-1-yl)benzoic acid
To a mixture of EXAMPLE 224C (1.78 g) in tetrahydrofuran (30 mL),
methanol (10 mL) and water (10 mL) was added LiOH.H.sub.2O (0.262
g). The mixture was stirred overnight. The mixture was then
neutralized with 5% aqueous HCl and exacted with ethyl acetate
(3.times.) and the combined organic layers were washed with brine
and dried over Na.sub.2SO.sub.4. Evaporation of solvent gave the
title compound.
Example 224E
4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-y-
l)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitropheny-
l}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 224D for EXAMPLE
1E and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.08 (s, 1H), 8.50 (d,
1H), 8.13 (d, 1H), 7.77 (dd, 1H), 7.52 (d, 1H), 7.34 (m, 4H), 7.04
(m, 4H), 6.78 (dd, 1H), 6.59 (dd, 1H), 6.35 (s, 1H), 6.13 (d, 1H),
4.59 (d, 1H), 3.74 (m, 2H), 3.39 (m, 1H), 3.03 (m, 7H), 2.68 (m,
3H), 2.41 (m, 4H), 2.17 (m, 7H), 2.00 (m, 3H), 1.71 (m, 3H).
Example 225
4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-y-
l)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidi-
n-4-yl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 224D for EXAMPLE
1E and EXAMPLE 173C for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.07 (s, 1H), 8.47 (d,
1H), 8.14 (d, 1H), 7.92 (s, 1H), 7.72 (dd, 1H), 7.52 (d, 1H), 7.46
(d, 1H), 7.33 (m, 4H), 7.07 (d, 2H), 6.98 (d, 1H), 6.77 (m, 1H),
6.58 (dd, 1H), 6.34 (s, 1H), 6.14 (d, 1H), 4.59 (m, 1H), 3.90 (dd,
2H), 3.70 (m, 1H), 3.01 (m, 8H), 2.71 (m, 6H), 2.56 (m, 8H), 2.19
(m, 4H), 1.94 (m, 3H), 1.56 (m, 3H).
Example 226
4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-y-
l)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitropheny-
l}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 224D for EXAMPLE
1E and EXAMPLE 174A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.13 (s, 1H), 9.13 (s,
1H), 8.52 (d, 1H), 7.83 (dd, 1H), 7.53 (t, 2H), 7.36 (m, 4H), 7.09
(m, 3H), 6.83 (dd, 1H), 6.61 (dd, 1H), 6.38 (s, 1H), 6.12 (d, 1H),
4.59 (d, 1H), 3.75 (m, 1H), 2.81 (m, 12H), 2.27 (m, 12H), 1.79 (m,
4H).
Example 227
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitroph-
enyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide
Example 227A
4-(1-indan-2-yl-piperidin-4-ylamino)-3-nitro-benzenesulfonamide
2-Aminoindane (12.84 g) and triethylamine (15.04 mL, 10.92 g) were
added to 1,4-dioxane (150 mL) and the mixture was stirred until the
solids were dissolved. 4-Chloro-3-nitrobenzenesulfonamide (12.77 g)
was added, and the mixture was heated to 90.degree. C. for 16
hours. The mixture was cooled and the precipitate vacuum was
filtered, washed with 20% methanol in dichloromethane, and washed
with 100% dichloromethane.
Example 227B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitroph-
enyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 227A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.20 (br s, 1H), 8.48 (d,
1H), 8.21 (d, 1H), 7.73 (dd, 1H), 7.54 (d, 1H), 7.34 (d, 2H),
7.26-7.21 (m, 3H), 7.16-7.12 (m, 2H), 7.09-7.02 (m, 3H), 6.95 (t,
2H), 6.68 (dd, 1H), 6.39 (d, 1H), 6.24 (m, 2H), 3.74 (m, 1H),
3.18-2.80 (m, 13H), 2.72 (br s, 2H), 2.16 (m, 6H), 2.03 (m, 2H),
1.95 (br s, 2H), 1.68 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 228
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitroph-
enyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 227A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.12 (br s, 1H), 8.55 (d,
1H), 8.23 (d, 1H), 7.79 (dd, 1H), 7.51 (d, 1H), 7.41-7.31 (m, 4H),
7.22 (m, 2H), 7.16-7.09 (m, 3H), 7.07-7.01 (m, 3H), 6.83 (dd, 1H),
6.63 (dd, 1H), 6.37 (t, 1H), 6.15 (d, 1H), 3.73 (m, 1H), 3.16-2.82
(m, 13H), 2.71 (br s, 2H), 2.16 (m, 6H), 2.02 (m, 2H), 1.95 (br s,
2H), 1.67 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 229
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-morpholin-4-ylcyclohexyl)methyl]amin-
o}-3-nitrophenyl)sulfonyl]benzamide
This example was prepared by substituting
(1-morpholinocyclohexyl)methanamine for
(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in
EXAMPLE 187B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.19 (s, 1H), 9.08 (s, 1H), 8.60 (d, 1H), 7.81 (dd, 1H),
7.51 (d, 1H), 7.43 (d, 1H), 7.39 (t, 1H), 7.33 (d, 2H), 7.16-7.18
(m, 2H), 7.03 (d, 2H), 6.88 (dd, 1H), 6.65 (dd, 1H), 6.40 (s, 1H),
6.13 (d, 1H), 3.60 (s, 4H), 3.42-3.43 (m, 2H), 3.01 (br s, 4H),
2.72 (br s, 2H), 2.57 (br s, 4H), 2.12-2.16 (m, 7H), 1.94 (br s,
2H), 1.46-1.60 (m, 12H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).
Example 230
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-ylmethyl)piper-
idin-4-yl]amino}phenyl)sulfonyl]benzamide
Example 230A
tert-butyl 1-(thiazol-2-ylmethyl)piperidin-4-ylcarbamate
This example was prepared by substituting thiazole-2-carbaldehyde
for EXAMPLE 27C and tert-butyl piperidin-4-ylcarbamate for
tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
Example 230B
1-(thiazol-2-ylmethyl)piperidin-4-amine
This example was prepared by substituting EXAMPLE 230A for EXAMPLE
1A in EXAMPLE 1B.
Example 230C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-ylmethyl)piper-
idin-4-yl]amino}phenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 230B for
(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in
EXAMPLE 187B. 11 NMR (500 MHz, dimethylsulfoxide-d.sub.6) S 11.14
(s, 1H), 8.23 (d, 1H), 7.76-7.79 (m, 2H), 7.65 (s, 1H), 7.53 (d,
1H), 7.38-7.40 (m, 2H), 7.34 (d, 2H), 7.17 (d, 1H), 7.11 (s, 1H),
7.04 (d, 2H), 6.82 (dd, 1H), 6.62 (d, 1H), 6.38 (s, 1H), 6.14 (d,
1H), 4.19 (s, 2H), 3.01 (s, 4H), 2.91-2.96 (m, 2H), 2.72 (s, 2H),
2.12-2.17 (m, 6H), 1.95-1.99 (m, 4H), 1.47-1.51 (m, 2H), 1.36-1.39
(m, 2H), 0.92 (s, 6H).
Example 231
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-4-ylmethyl)piper-
idin-4-yl]amino}phenyl)sulfonyl]benzamide
Example 231A
tert-butyl 1-(thiazol-4-ylmethyl)piperidin-4-ylcarbamate
This example was prepared by substituting thiazole-4-carbaldehyde
for EXAMPLE 27C and tert-butyl piperidin-4-ylcarbamate for
tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
Example 231B
1-(thiazol-4-ylmethyl)piperidin-4-amine
This example was prepared by substituting EXAMPLE 231A for EXAMPLE
1A in EXAMPLE 1B.
Example 231C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-4-ylmethyl)piper-
idin-4-yl]amino}phenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 231B for
(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in
EXAMPLE 187B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.11 (s, 1H), 9.06 (s, 1H), 8.21 (d, 1H), 7.98 (s, 1H),
7.77 (dd, 1H), 7.54 (d, 1H), 7.33-7.38 (m, 4H), 7.13 (d, 2H),
7.03-7.07 (m, 3H), 6.79 (dd, 1H), 6.60 (dd, 1H), 6.37 (s, 1H), 6.14
(d, 1H), 4.23 (s, 2H), 2.99 (s, 4H), 2.89-2.94 (m, 2H), 2.71 (s,
2H), 2.12-2.17 (m, 6H), 1.95-1.99 (m, 4H), 1.47-1.51 (m, 2H),
1.36-1.39 (m, 2H), 0.92 (s, 6H).
Example 232
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3-n-
itrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting
(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)methanol for
(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in
EXAMPLE 187B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.17 (s, 1H), 9.10 (t, 1H), 8.59 (d, 1H), 7.81 (dd, 1H),
7.51 (d, 1H), 7.42 (d, 1H), 7.39 (t, 1H), 7.16-7.18 (m, 2H), 7.03
(d, 2H), 6.87 (dd, 1H), 6.65 (d, 1H), 6.39 (s, 1H), 6.14 (d, 1H),
5.22 (t, 1H), 3.51-3.62 (m, 6H), 3.19 (d, 2H), 3.03 (s, 4H), 2.72
(s, 2H), 2.12-2.17 (m, 6H), 1.94 (s, 2H), 1.45-1.49 (m, 4H),
1.36-1.39 (m, 2H), 0.92 (s, 6H).
Example 233
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[4-(2-hydroxyethyl)piperazin-1-yl]amino}-3-nitrophenyl)sulfon-
yl]-2-(1H-indol-5-yloxy)benzamide
Example 233A
4-(4-(2-hydroxyethyl)piperazin-1-ylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting
2-(4-aminopiperazin-1-yl)ethanol for
(tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 1F.
Example 233B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[4-(2-hydroxyethyl)piperazin-1-yl]amino}-3-nitrophenyl)sulfon-
yl]-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 233A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.15 (s, 1H), 9.17 (m, 1H), 8.53 (d, 1H), 7.83 (dd, 1H),
7.56 (d, 1H), 7.51 (d, 1H), 7.36 (m, 4H), 7.13 (m, 1H), 7.03 (m,
2H), 6.84 (dd, 1H), 6.62 (dd, 1H), 6.38 (m, 1H), 6.12 (m, 1H), 4.57
(m, 1H), 3.54 (m, 2H), 2.95 (m, 10H), 2.71 (s, 2H), 2.57 (m, 2H),
2.15 (m, 6H), 1.94 (s, 2H), 1.38 (t, 2H), 0.93 (s, 6H)
Example 234
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3-n-
itrophenyl)sulfonyl]benzamide
Example 234A
(S)-tert-butyl 1-methylpyrrolidin-3-ylcarbamate
To a mixture of (S)-tert-butyl 1-methylpyrrolidin-3-ylcarbamate
(438 mg) in methanol (10 mL) was added 37% formaldehyde mixture in
water (0.53 mL) and sodium borohydride (267 mg). The reaction
mixture was stirred overnight at room temperature and then
concentrated. The residue was dissolved in chloroform (15 mL),
washed with brine and NaHCO.sub.3 solution, dried over MgSO.sub.4,
filtered and concentrated. The title compound was used in the next
step without further purification.
Example 234B
(S)-1-methylpyrrolidin-3-amine
This example was prepared by substituting EXAMPLE 234A for EXAMPLE
1A in EXAMPLE 1B.
Example 234C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3-n-
itrophenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 234B for
1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 310B for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 10.98 (s, 1H), 8.38
(d, 1H), 8.16 (d, 1H), 7.64 (dd, 1H), 7.53 (d, 1H), 7.34 (d, 2H),
7.28 (m, 2H), 7.05 (d, 2H), 6.89 (d, 1H), 6.72 (d, 1H), 6.68 (dd,
1H), 6.53 (dd, 1H), 6.29 (t, 1H), 6.15 (d, 1H), 4.14 (br s, 1H),
2.93 (m, 4H), 2.71 (m, 4H), 2.33 (m, 2H), 2.27 (s, 3H), 2.16 (m,
6H), 1.95 (s, 2H), 1.61 (m, 1H), 1.38 (t, 2H), 1.24 (br s, 1H),
0.92 (s, 6H).
Example 235
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(3-fluoropropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfon-
yl]-2-(1H-indol-5-yloxy)benzamide
Example 235A
4-(1-(3-fluoropropyl)piperidin-4-ylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting 1-fluoro-3-iodopropane
for 1,1,1-trifluoro-4-iodobutane in EXAMPLE 210A.
Example 235B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(3-fluoropropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfon-
yl]-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 235A for EXAMPLE
1F and EXAMPLE 26C for EXAMPLE 1E in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.12 (s, 1H), 10.89 (br s,
1H), 8.48 (d, 1H), 8.152 (d, 1H), 7.79 (dd, 1H), 7.50 (d, 1H), 7.34
(m, 4H), 7.03 (m, 4H), 6.83 (dd, 1H), 6.63 (dd, 1H), 6.37 (m, 1H),
6.15 (d, 1H), 3.71 (br s, 1H), 3.01 (m, 4H), 2.92 (m, 2H), 2.72 (m,
2H), 2.56 (m, 1H), 2.30 (m, 2H), 2.16 (m, 6H), 1.95 (m, 5H), 1.83
(m, 1H), 1.68 (m, 2H), 1.38 (m, 2H), 1.24 (br s, 1H), 0.92 (s,
6H).
Example 236
4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydrox-
ymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-
-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 218E for EXAMPLE
26C in EXAMPLE 177. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.17 (s, 2H), 8.62 (s, 1H),
8.58 (s, 1H), 7.78 (d, 1H), 7.52 (d, 1H), 7.39-7.42 (m, 2H), 7.33
(d, 1H), 7.14 (s, 1H), 7.09 (d, 1H), 7.04 (d, 1H), 6.86 (d, 1H),
6.62 (d, 1H), 6.39 (s, 1H), 6.14 (s, 1H), 4.46 (m, 1H), 3.85 (dd,
2H), 3.17-3.25 (m, 8H), 2.76 (br s, 2H), 2.58 (br s. 2H), 1.89-2.01
(m, 6H), 1.80 (br, 2H), 1.29-1.38 (m, 2H), 0.91 (s, 6H).
Example 237
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfo-
nyl]-4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl)}-3-(-
hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)benzamide
Example 237A
4-((4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting
4-(aminomethyl)tetrahydro-2H-pyran-4-amine for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 237B
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfo-
nyl]-4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(h-
ydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 218E for EXAMPLE
26C and EXAMPLE 237A for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.46 (s, 1H), 11.19
(s, 1H), 8.16 (d, 1H), 8.51-8.55 (m, 1H), 8.11 (s, 2H), 7.88 (d,
1H), 7.53 (d, 1H), 7.32-7.43 (m, 5H), 7.15 (s, 1H), 7.09 (d, 1H),
6.85 (dd, 1H), 6.68 (s, 1H), 6.40 (s, 1H), 6.21 (s, 1H), 3.81-3.82
(m, 2H), 3.70-3.72 (m, 4H), 3.10 (br s, 2H), 2.02-2.09 (m, 2H),
1.60-1.85 (m, 2H), 1.66-1.73 (m, 2H), 1.35-1.38 (m, 2H), 0.93 (s,
6H).
Example 238
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(1-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-
-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting
1-(aminomethyl)cyclohexanol for
(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in
EXAMPLE 187B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.17 (s, 2H), 8.69 (t, 1H), 8.60 (d, 1H), 7.80 (dd, 1H),
7.51 (d, 1H), 7.39-7.43 (m, 2H), 7.33 (d, 2H), 7.17 (d, 2H), 7.14
(d, 1H), 7.03 (d, 2H), 6.87 (dd, 1H), 6.65 (d, 1H), 6.40 (s, 1H),
6.14 (d, 1H), 4.73 (s, 1H), 3.03 (s, 4H), 2.74 (s, 2H), 2.12-2.18
(m, 6H), 1.94 (s, 2H), 1.54-1.58 (m, 4H), 1.36-1.43 (m, 7H), 0.92
(s, 6H).
Example 239
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sul-
fonyl)benzamide
This example was prepared by substituting EXAMPLE 179A for EXAMPLE
1F and EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.25 (s, 2H), 8.57 (m,
1H), 8.50 (d, 1H), 7.70 (dd, 1H), 7.52 (d, 1H), 7.34 (d, 2H), 7.28
(t, 1H), 7.17 (d, 1H), 7.05 (m, 3H), 6.97 (t, 1H), 6.71 (dd, 1H),
6.42 (d, 1H), 6.26 (m, 2H), 3.58 (m, 4H), 3.31 (s, 3H), 3.05 (m,
4H), 2.73 (s, 2H), 2.17 (m, 6H), 1.96 (s, 2H), 1.38 (t, 2H), 0.93
(s, 6H)
Example 240
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide
Example 240A
4-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-ylamino)-3-nitrobenzenesulfonami-
de
This example was prepared by substituting
(4-aminotetrahydro-2H-pyran-4-yl)methanol for
(tetrahydropyran-4-yl)methylamine and
4-fluoro-3-nitrobenzenesulfonamide for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1F.
Example 240B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophen-
yl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 240A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.14 (s, 2H), 8.63 (d, 1H), 8.50 (s, 1H), 7.92 (s, 1H),
7.79 (dd, 1H), 7.52 (d, 1H), 7.39-7.43 (m, 2H), 7.33-7.34 (m, 3H),
7.18 (s, 1H), 7.03 (d, 2H), 6.87 (dd, 1H), 6.65 (dd, 1H), 6.40 (s,
1H), 6.13 (d, 1H), 5.04 (t, 1H), 3.67-3.72 (m, 4H), 3.56 (t, 2H),
3.02 (s, 4H), 2.72 (br, 2H), 2.12-2.16 (m, 6H), 1.94-2.01 (m, 3H),
1.81-1.85 (m, 2H), 1.36-1.39 (m, 2H), 1.24 (m, 6H), 0.92 (s,
6H).
Example 241
4-(4-({[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophe-
nyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 240A for EXAMPLE
1F and EXAMPLE 55B for EXAMPLE 26 C in EXAMPLE 177. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.26 (s, 2H), 8.55
(d, J=2.14 Hz, 1H), 8.48 (s, 1H), 7.66 (dd, 1H), 7.54 (d, 1H), 7.34
(d, 2H), 7.27-7.29 (m, 2H), 7.19 (d, 2H), 7.03 (d, 2H), 6.99 (t,
1H), 6.70 (dd, 1H), 6.44 (d, 1H), 6.27 (s, 1H), 5.04 (t, 1H),
3.67-3.72 (m, 4H), 3.56 (t, 2H), 3.04 (s, 4H), 2.74 (s, 2H),
2.12-2.17 (m, 6H), 1.95-2.01 (m, 5H), 1.80-1.85 (m, 2H), 1.38 (t,
2H), 1.24 (m, 4H), 0.92 (s, 6H).
Example 242
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2-hydroxy-1-tetrahydro-2H-pyran-4-ylethyl)amino]-3-nitrophen-
yl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting
2-amino-2-(tetrahydro-2H-pyran-4-yl)ethanol for
(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in
EXAMPLE 187B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.18 (s, 1H), 8.60 (d, 1H), 8.57 (d, 1H), 7.79 (dd, 1H),
7.52 (d, 1H), 7.43 (d, 1H), 7.40 (t, 1H), 7.33 (d, 2H), 7.23 (d,
1H), 7.19 (d, 1H), 7.03 (d, 2H), 6.88 (dd, 1H), 6.65 (dd, 1H), 6.41
(s, 1H), 6.13 (d, 1H), 5.03 (t, 1H), 3.83-3.87 (m, 2H), 3.56-3.73
(m, 4H), 3.26 (t, 2H), 3.03 (s, 4H), 2.72 (s, 2H), 2.12-2.17 (br s,
4H), 1.58-1.62 (m, 2H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).
Example 243
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(H-indol-5-yloxy)-N-{[3-nitro-4-({1-[2-(1H-pyrazol-1-yl)ethyl]pipe-
ridin-4-yl}amino)phenyl]sulfonyl}benzamide
Example 243A
4-(1-(2-(1H-pyrazol-1-yl)ethyl)piperidin-4-ylamino)-3-nitrobenzenesulfonam-
ide
This example was prepared by substituting
1-(2-bromoethyl)-1H-pyrazole for 1,1,1-trifluoro-4-iodobutane in
EXAMPLE 210A. After concentrating the reaction mixture, the title
compound was collected by filtration of the ether slurry.
Example 243B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-({1-[2-(1H-pyrazol-1-yl)ethyl]pip-
eridin-4-yl}amino)phenyl]sulfonyl}benzamide
This example was prepared by substituting EXAMPLE 243A for EXAMPLE
1F and EXAMPLE 26C for EXAMPLE 1E in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.25 (br s, 1H), 11.14 (s,
1H), 8.55 (d, 1H), 8.22 (d, 1H), 7.74 (m, 2H), 7.50 (d, 1H), 7.40
(m, 3H), 7.33 (d, 2H), 7.10 (m, 1H), 7.03 (d, 2H), 6.83 (dd, 1H),
6.63 (dd, 1H), 6.38 (t, 1H), 6.22 (t, 1H), 6.15 (d, 1H), 4.24 (t,
2H), 3.65 (br s, 1H), 3.02 (m, 4H), 2.78 (m, 6H), 2.27 (m, 2H),
2.16 (m, 6H), 1.94 (m, 3H), 1.60 (m, 2H), 1.38 (t, 2H), 1.23 (br s,
1H), 0.92 (s, 6H).
Example 244
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)-
amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
26 C in EXAMPLE 177. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.26 (s, 2H), 8.61 (t, 1H),
8.50 (d, 1H), 7.69 (dd, 1H), 7.28 (t, 1H), 7.18 (d, 2H), 7.07 (d,
1H), 7.04 (d, 2H), 6.97 (t, 1H), 6.71 (dd, 1H), 6.43 (d, 1H), 6.28
(d, 1H), 6.26 (d, 1H), 5.04 (t, 1H), 3.85 (dd, 2H), 3.25-3.31 (m,
6H), 3.05 (s, 4H), 2.74 (s, 2H), 2.14-2.18 (m, 6H), 1.87-1.90 (m,
2H), 1.61-1.63 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 245
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfonyl}benz-
amide
Example 245A
4-(methylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting methanamine for
(tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 1F.
Example 245B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfonyl}benz-
amide
This example was prepared by substituting EXAMPLE 245A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.12 (m, 2H), 8.54 (m, 2H), 7.76 (m, 1H), 7.51 (d, 1H),
7.35 (m, 4H), 7.06 (m, 3H), 6.85 (m, 2H), 6.63 (d, 1H), 6.37 (m,
1H), 6.15 (d, 1H), 3.01 (m, 4H), 2.96 (d, 3H), 2.71 (s, 2H), 2.15
(m, 6H), 1.94 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H)
Example 246
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfonyl}benz-
amide
This example was prepared by substituting EXAMPLE 245A for EXAMPLE
1F and EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.32 (br s, 1H), 11.20 (br
s, 1H), 8.54 (br s, 1H), 8.46 (s, 1H), 7.70 (dd, 1H), 7.53 (d, 1H),
7.34 (d, 2H), 7.26 (m, 1H), 7.14 (d, 1H), 7.04 (d, 2H), 6.94 (t,
1H), 6.87 (m, 1H), 6.67 (m, 1H), 6.37 (m, 1H), 6.25 (m, 2H), 3.02
(m, 4H), 2.97 (d, 3H), 2.72 (s, 2H), 2.16 (m, 6H), 1.94 (s, 2H),
1.38 (t, 2H), 0.93 (s, 6H).
Example 247
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4--
yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzam-
ide
This example was prepared by substituting EXAMPLE 175E for EXAMPLE
1E and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (500
MHz, PYRIDINE-d.sub.5) .delta. ppm 12.45 (s, 1H), 9.24 (d, 1H),
8.96 (t, 1H), 8.26 (dd, 1H), 8.16 (d, 1H), 7.65 (d, 1H), 7.46 (m,
5H), 7.35 (t, 1H), 7.30 (d, 2H), 7.24 (d, 1H), 7.15 (t, 1H), 6.86
(d, 1H), 6.79 (d, 1H), 6.74 (m, 2H), 6.61 (d, 1H), 3.78 (t, 4H),
3.41 (q, 1H), 3.31 (m, 2H), 2.94 (m, 4H), 2.34 (m, 6H), 2.24 (m,
2H), 2.10 (m, 2H), 1.72 (m, 2H), 1.15 (d, 3H).
Example 248
4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-y-
l)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)ami-
no]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 224D for EXAMPLE
1E in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.17 (s, 1H), 8.60 (m, 1H), 7.80 (dd, 1H), 7.52 (d, 1H),
7.38 (m, 4H), 7.11 (m, 4H), 6.87 (dd, 1H), 6.65 (dd, 1H), 6.40 (s,
1H), 6.13 (d, 1H), 4.59 (d, 1H), 3.85 (m, 2H), 3.28 (m, 6H), 3.03
(m, 2H), 2.72 (m, 2H), 2.18 (m, 3H), 1.87 (m, 3H), 1.53 (m, 5H),
1.26 (m, 7H).
Example 249
4-(4-{[2-(4-chlorophenyl)-5-morpholin-4-ylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmet-
hyl)amino]phenyl}sulfonyl)benzamide
Example 249A
8-chloro-1,4-dioxaspiro[4.5]dec-7-ene-7-carbaldehyde
This example was prepared by substituting
1,4-dioxaspiro[4.5]decan-8-one for
4-(tert-butyldimethylsilyloxy)cyclohexanone in EXAMPLE 224A.
Example 249B
8-(4-chlorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carbaldehyde
This example was prepared by substituting EXAMPLE 249A for EXAMPLE
224A in EXAMPLE 224B.
Example 249C
methyl
2-(1H-indol-5-yloxy)-4-(4-((8-(4-chlorophenyl)-1,4-dioxaspiro[4.5]d-
ec-7-en-7-yl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 249B for EXAMPLE
224B in EXAMPLE 224C.
Example 249D
2-(1H-indol-5-yloxy)-4-(4-((8-(4-chlorophenyl)-1,4-dioxaspiro[4.5]dec-7-en-
-7-yl)methyl)piperazin-1-yl)benzoic acid
The title compound was prepared by substituting EXAMPLE 249C for
EXAMPLE 224C in EXAMPLE 224D.
Example 249E
2-(1H-indol-5-yloxy)-4-(4-((8-(4-chlorophenyl)-1,4-dioxaspiro[4.5]dec-7-en-
-7-yl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methy-
lamino)phenylsulfonyl)benzamide
This example was prepared by substituting EXAMPLE 249D for EXAMPLE
1E in EXAMPLE 1G.
Example 249F
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5-oxocyclohex-1-enyl)methyl-
)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)pheny-
lsulfonyl)benzamide
A mixture of EXAMPLE 249E (20 mg) and pyridinium p-toluenesulfonate
(16.8 mg) in acetone/H.sub.2O (1:1, 3 mL) was heated in a microwave
to 135.degree. C. for 8 minutes.
The mixture was diluted with dichloromethane (100 mL), washed with
water and brine, and dried over Na.sub.2SO.sub.4. Filtration and
evaporation of solvent gave the product.
Example 249G
4-(4-{[2-(4-chlorophenyl)-5-morpholin-4-ylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmet-
hyl)amino]phenyl}sulfonyl)benzamide
To a mixture of EXAMPLE 249F (120 mg) in dichloromethane (2 mL) and
methanol (0.5 mL) was added morpholine (37 mg) and 2-picoline
borane complex (15.04 mg). The mixture was stirred overnight. The
mixture was then diluted with dichloromethane (200 mL) and washed
with aqueous NaHCO.sub.3, water, and brine, and dried over
Na.sub.2SO.sub.4. The residue, after evaporation of solvent, was
dissolved in dichloromethane and chromatographed with 0-10% 7N
NH.sub.3 in 5% methanol in dichloromethane to give the title
compound. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.15 (s, 1H), 8.58 (m, 2H), 7.79 (dd, 1H), 7.53 (m, 1H), 7.35 (m,
4H), 7.17 (m, 1H), 7.07 (m, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.39
(s, 1H), 6.13 (d, 1H), 3.84 (m, 2H), 3.58 (m, 5H), 3.01 (m, 5H),
2.63 (m, 6H), 2.10 (m, 14H), 1.61 (m, 3H), 1.26 (m, 3H).
Example 250
N-[(4-{[(1-aminocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2--
(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(-
1H-indol-5-yloxy)benzamide
This example was prepared by substituting
1-(aminomethyl)cyclohexanamine, 2hydrochloric acid for
(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in
EXAMPLE 187B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.04 (s, 1H), 8.47 (d, 1H), 8.39 (s, 1H), 7.79 (dd, 1H),
7.55 (d, 1H), 7.31-7.34 (m, 4H), 6.99-7.08 (m, 4H), 6.73 (dd, 1H),
6.65 (dd, 1H), 6.33 (s, 1H), 6.12 (d, 1H), 3.55 (d, 2H), 2.94 (s,
4H), 2.71 (s, 2H), 2.14-2.17 (m, 6H), 1.95 (s, 2H), 1.50-1.64 (m,
8H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).
Example 251
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxopyrrolidin-1-yl)ethyl]a-
mino)}phenyl)sulfonyl]benzamide
This example was prepared by substituting
1-(2-aminoethyl)pyrrolidin-2-one for
(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in
EXAMPLE 187B. 1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.17 (s, 1H), 8.58-8.60 (m, 2H), 7.84 (dd, 1H), 7.51 (d, 1H),
7.39-7.32 (m, 2H), 7.33 (d, 2H), 7.18 (d, 1H), 7.12 (d, 1H), 7.03
(d, 2H), 6.87 (dd, 1H), 6.65 (dd, 1H), 6.40 (s, 1H), 6.17 (d, 1H),
3.53-3.56 (m, 2H), 3.45 (t, 2H), 3.39 (t, 2H), 3.04 (s, 4H), 2.74
(s, 2H), 2.11-2.18 (m, 8H), 1.94 (s, 2H), 1.83-1.90 (m, 2H), 1.38
(t, 2H), 0.92 (s, 6H).
Example 252
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-5--
yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)benzamide
Example 252A
methyl
2-(1H-indol-5-yloxy)-4-(4-(1-(4'-chlorobiphenyl-2-yl)ethyl)piperazi-
n-1-yl)benzoate
The title compound was prepared as described in EXAMPLE 175D by
replacing ethyl 2-(1H-indol-4-yloxy)-4-fluorobenzoate with EXAMPLE
26A.
Example 252B
2-(1H-indol-5-yloxy)-4-(4-(1-(4'-chlorobiphenyl-2-yl)ethyl)piperazin-1-yl)-
benzoic acid
The title compound was prepared as described in EXAMPLE 175E by
replacing EXAMPLE 175D with v 252A.
Example 252C
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-5--
yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)benzamide
The title compound was prepared as described in EXAMPLE 175F by
replacing EXAMPLE 175E with EXAMPLE 252B. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.20 (s, 1H), 11.16 (s, 1H),
8.62 (t, 1H), 8.58 (d, 1H), 7.79 (dd, 1H), 7.48-7.54 (m, 2H), 7.45
(d, 2H), 7.35-7.41 (m, 3H), 7.25-7.29 (m, 3H), 7.15 (d, 1H),
7.08-7.13 (m, 2H), 6.86 (dd, 1H), 6.63 (dd, 1H), 6.38 (s, 1H), 6.13
(d, 1H), 3.85 (dd, 2H), 3.22-3.32 (m, 4H), 3.00 (s, 4H), 2.33 (s,
2H), 2.18 (s, 2H), 1.84-1.95 (m, 1H), 1.56-1.66 (m, 2H), 1.21-1.31
(m, 3H), 1.16 (d, 3H).
Example 253
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl-
)amino]phenyl}sulfonyl)benzamide
Example 253A
1-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)ethanol
To a mixture of EXAMPLE 218A (3.52 g) in tetrahydrofuran (30 ml)
was slowly added methylmagnesium chloride (3 M in tetrahydrofuran,
7.08 ml) at -78.degree. C. After the addition was completed, the
reaction mixture was stirred at 0.degree. C. for 30 minutes and
ice-water was added. The resulting mixture was extracted with
dichloromethane and the organic layer was dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified by
flash chromatography, eluting with 0-100% dichloromethane in hexane
to provide the title compound.
Example 253B
1-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)ethanone
To a mixture of EXAMPLE 253A (1.18 g) in dichloromethane (20 ml)
was slowly added Dess-Martin Periodinane (2.457 g). The reaction
mixture was stirred at room temperature for 3 hours and diluted
with ether. The resulting mixture was washed with aqueous NaOH and
water. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated. The residue was purified by flash chromatography,
eluting with 0-100% dichloromethane in hexane to provide the title
compound.
Example 253C
tert-butyl
4-(1-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)ethyl)pipe-
razine-1-carboxylate
EXAMPLE 253B (2.06 g) and tert-butyl piperazine-1-carboxylate (2.92
g) was treated with titanium(IV) isopropoxide (4.59 ml) at ambient
temperature for 24 hours. Sodium cyanoborohydride (0.493 g) in
methanol (10 ml) was added. The reaction mixture was stirred
overnight and aqueous NaOH was added. The resulting mixture was
diluted with ethyl acetate (300 ml). The precipitate was filtered
off and washed with ethyl acetate. The organic layer was separated
and washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was dissolved in dichloromethane and
loaded onto a silica gel column, eluted with 0-25% ethyl acetate in
dichloromethane to provide the title compound.
Example 253D
1-(1-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)ethyl)piperazine
The title compound was prepared as described in EXAMPLE 175C by
replacing EXAMPLE 175B with EXAMPLE 253C.
Example 253E
ethyl
2-(1H-indol-5-yloxy)-4-(4-(1-(2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-enyl)ethyl)piperazin-1-yl)benzoate
The title compound was prepared as described in EXAMPLE 175D by
replacing ethyl 2-(1H-indol-4-yloxy)-4-fluorobenzoate and EXAMPLE
175C with EXAMPLE 26A and EXAMPLE 253D, respectively.
Example 253F
2-(1H-indol-5-yloxy)-4-(4-(1-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-
yl)ethyl)piperazin-1-yl)benzoic acid
The title compound was prepared as described in EXAMPLE 175E by
replacing EXAMPLE 175D with EXAMPLE 253E.
Example 253G
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl-
)amino]phenyl}sulfonyl)benzamide
The title compound was prepared as described in EXAMPLE 177 by
replacing EXAMPLE 26C with EXAMPLE 253F. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.18 (s, 2H), 8.62 (t, 1H),
8.59 (d, 1H), 7.81 (dd, 1H), 7.52 (d, 1H), 7.38-7.44 (m, 2H), 7.34
(d, 2H), 7.17 (d, 1H), 7.11 (d, 1H), 7.01 (d, 2H), 6.87 (dd, 1H),
6.65 (dd, 1H), 6.40 (t, 1H), 6.13 (d, 1H), 3.85 (dd, 2H), 3.22-3.31
(m, 4H), 3.02 (s, 4H), 2.57-2.73 (m, 1H), 2.23 (s, 4H), 1.78-2.15
(m, 5H), 1.57-1.65 (m, 2H), 1.32-1.42 (m, 2H), 1.19-1.31 (m, 2H),
1.01 (d, 3H), 0.91 (d, 6H).
Example 254
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrop-
henyl}sulfonyl)benzamide
The title compound was prepared as described in EXAMPLE 175F by
replacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 253F and EXAMPLE
174A. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.15 (s, 1H), 9.19 (s, 1H), 8.54 (d, 1H), 7.85 (dd, 1H), 7.57 (d,
1H), 7.52 (d, 1H), 7.37-7.41 (m, 2H), 7.34 (d, 2H), 7.14 (d, 1H),
7.01 (d, 2H), 6.84 (dd, 1H), 6.62 (dd, 1H), 6.39 (s, 1H), 6.12 (d,
1H), 2.81-3.04 (m, 10H), 2.58-2.67 (m, 1H), 2.29-2.45 (m, 5H),
2.15-2.28 (m, 4H), 1.92-2.13 (m, 3H), 1.82 (d, 1H), 1.29-1.41 (m,
2H), 1.00 (d, 3H), 0.91 (d, 6H).
Example 255
4-{4-[(1R)-1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-ind-
ol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}su-
lfonyl)benzamide
The title compound was obtained by the separation of the racemic
mixture of EXAMPLE 175F on a chiral HPLC. .sup.1H NMR (500 MHz,
dimethysulfoxide-d.sub.6) .delta. 11.31 (1H, s), 11.25 (1H, s),
8.62 (1H, t), 8.50 (1H, d), 7.68 (1H, dd), 7.53 (2H, d), 7.46 (2H,
d), 7.37 (1H, t), 7.24-7.31 (4H, m), 7.17 (1H, d), 7.12 (1H, dd),
7.07 (1H, d), 6.96 (1H, t), 6.69 (1H, dd), 6.42 (1H, d), 6.26 (2H,
s), 3.85 (2H, dd), 3.21-3.33 (5H, m), 3.01 (4H, s), 2.29-2.39 (2H,
m), 2.15-2.22 (2H, m), 1.83-1.94 (1H, m), 1.57-1.68 (2H, m),
1.22-1.31 (2H, m), 1.17 (3H, d).
Example 256
4-{4-[(1S)-1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-ind-
ol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}su-
lfonyl)benzamide
The title compound was obtained by the separation of the racemic
mixture of EXAMPLE 175F on a chiral HPLC. .sup.1H NMR (500 MHz,
dimethysulfoxide-d.sub.6) .delta. 11.31 (1H, s), 11.25 (1H, s),
8.62 (1H, t), 8.50 (1H, d), 7.68 (1H, dd), 7.53 (2H, d), 7.46 (2H,
d), 7.37 (1H, t), 7.24-7.31 (4H, m), 7.17 (1H, d), 7.12 (1H, dd),
7.07 (1H, d), 6.96 (1H, t), 6.69 (1H, dd), 6.42 (1H, d), 6.26 (2H,
s), 3.85 (2H, dd), 3.21-3.33 (5H, m), 3.01 (4H, s), 2.29-2.39 (2H,
m), 2.15-2.22 (2H, m), 1.83-1.94 (1H, m), 1.57-1.68 (2H, m),
1.22-1.31 (2H, m), 1.17 (3H, d).
Example 257
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrop-
henyl}sulfonyl)benzamide
The title compound was prepared as described in EXAMPLE 175F by
replacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 253F and EXAMPLE
7A. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.79
(t, 1H), 8.57 (d, 1H), 7.80 (dd, 1H), 7.51 (d, 1H), 7.37-7.44 (m,
2H), 7.34 (d, 2H), 7.15 (d, 1H), 7.06 (d, 1H), 7.01 (d, 2H), 6.85
(dd, 1H), 6.63 (dd, 1H), 6.39 (s, 1H), 6.13 (d, 1H), 3.60 (t, 4H),
3.43 (q, 2H), 3.01 (s, 4H), 2.63 (d, 1H), 2.33-2.47 (m, 6H), 2.22
(d, 4H), 1.94-2.15 (m, 3H), 1.75-1.86 (m, 3H), 1.32-1.40 (m, 2H),
1.00 (d, 3H), 0.91 (s, 3H), 0.90 (s, 3H).
Example 258
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-
-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpipe-
ridin-4-yl)amino]phenyl}sulfonyl)benzamide
The title compound was prepared as described in EXAMPLE 175F by
replacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 253F and EXAMPLE
173C. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.12 (s, 1H), 8.53 (d, 1H), 8.19 (d, 1H), 7.79 (dd, 1H), 7.52 (d,
1H), 7.32-7.40 (m, 4H), 6.99-7.12 (m, 4H), 6.81 (dd, 1H), 6.60 (dd,
1H), 6.37 (s, 1H), 6.13 (d, 1H), 3.92 (dd, 2H), 3.72 (s, 1H),
3.26-3.31 (m, 2H), 2.98 (s, 6H), 2.77 (s, 1H), 2.54-2.66 (m, 3H),
2.15-2.30 (m, 4H), 1.94-2.14 (m, 5H), 1.73-1.87 (m, 3H), 1.57-1.68
(m, 2H), 1.44-1.54 (m, 2H), 1.31-1.40 (m, 2H), 1.00 (d, 3H), 0.91
(d, 2H).
Example 259
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(H-indol-5-
-yloxy)benzamide
Example 259A
4-(cyclohexylmethylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting cyclohexylmethylamine for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 259B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol--
5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 259A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.10 (s, 1H), 8.53 (m, 1H), 8.52 (d, 1H), 7.72 (dd, 1H),
7.44 (d, 1H), 7.32, (d, 1H), 7.31 (dd, 1H), 7.26 (d, 2H), 7.08 (d,
1H), 6.99 (d, 1H), 6.96 (d, 2H), 6.80 (dd, 1H), 6.58 (dd, 1H), 6.32
(s, 1H), 6.07 (d, 1H), 3.18 (t, 2H), 2.96 (br m, 4H), 2.65 (d, 2H),
2.06 (br m, 6H), 1.87 (s, 2H), 1.63 (m, 4H), 1.56 (m, 2H), 1.30 (t,
2H), 1.11 (m, 2H), 0.91 (m, 3H), 0.85 (s, 6H).
Example 260
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfo-
nyl}benzamide
Example 260A
4-(morpholinoamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting morpholin-4-amine for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A.
Example 260B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfo-
nyl}benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 260A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (500
MHz, pyridine-d.sub.5) .delta. 9.28 (s, 1H), 9.25 (d, 1H), 8.39
(dd, 1H), 8.18 (d, 1H), 7.66 (d, 1H), 7.52-7.56 (m, 2H), 7.40-7.46
(m, 3H), 7.09 (dd, 1H), 7.06 (d, 2H), 6.73 (dd, 1H), 6.60 (s, 1H),
6.54 (d, 1H), 3.87 (s, 2H), 3.74 (d, 2H), 3.00-3.08 (m, 4H), 2.89
(d, 4H), 2.76 (s, 2H), 2.24 (t, 2H), 2.08-2.15 (m, 4H), 1.97 (s,
2H), 1.38 (t, 2H), 0.93 (s, 6H).
Example 261
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-3-ylmethyl)-
amino]phenyl}sulfonyl)benzamide
The title compound was prepared as described in EXAMPLE 175F by
replacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE
180A, respectively. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.17 (s, 2H), 8.45-8.70 (m,
2H), 7.80 (dd, 1H), 7.51 (d, 1H), 7.38-7.42 (m, 2H), 7.33 (d, 2H),
7.16 (d, 1H), 7.07 (d, 1H), 7.03 (d, 2H), 6.86 (dd, 1H), 6.65 (dd,
1H), 6.39 (s, 1H), 6.14 (d, 1H), 3.79 (dd, 1H), 3.68-3.75 (m, 1H),
3.23-3.38 (m, 3H), 3.18 (dd, 1H), 3.03 (s, 4H), 2.72 (s, 2H),
2.07-2.21 (m, 6H), 1.79-1.96 (m, 4H), 1.57-1.64 (m, 1H), 1.41-1.51
(m, 1H), 1.37 (t, 2H), 1.22-1.33 (m, 1H), 0.92 (s, 6H).
Example 262
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfo-
nyl}benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 260A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (500
MHz, pyridine-d.sub.5) .delta. 12.45 (s, 1H), 9.26 (s, 1H), 9.17
(d, 1H), 8.27 (dd, 1H), 8.17 (d, 1H), 7.61 (d, 1H), 7.48 (t, 1H),
7.45 (d, 2H), 7.39 (d, 1H), 7.05-7.13 (m, 3H), 6.71-6.81 (m, 3H),
6.67 (d, J=2.1 Hz, 1H), 3.87 (s, 2H), 3.61-3.78 (m, 2H), 2.99-3.08
(m, 4H), 2.89 (d, 4H), 2.76 (s, 2H), 2.25 (t, 2H), 2.08-2.16 (m,
4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).
Example 263
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)ph-
enyl]sulfonyl}benzamide
This example was prepared by substituting
tetrahydro-2H-pyran-4-amine, hydrochloric acid for
(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in
EXAMPLE 187B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.15 (s, 2H), 8.57 (d, 1H), 8.24 (d, 1H), 7.78 (dd, 1H),
7.49 (d, 1H), 7.37-7.40 (m, 3H), 7.32 (d, 2H), 7.12-7.16 (m, 2H),
7.22 (d, 2H), 6.84 (dd, 1H), 6.64 (dd, 1H), 6.37 (s, 1H), 6.13 (d,
1H), 3.85-3.87 (m, 2H), 3.45 (t, 2H), 3.02 (s, 4H), 2.71 (s, 2H),
2.11-2.16 (m, 7H), 1.87-1.93 (m 4H), 1.58-1.62 (m, 2H), 1.36 (t,
2H), 0.90 (s, 6H).
Example 264
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3-methyloxetan-3-yl)methyl]amino}-3-ni-
trophenyl)sulfonyl]benzamide
This example was prepared by substituting
(3-methyloxetan-3-yl)methanamine for
(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in
EXAMPLE 187B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.14 (s, 2H), 8.67 (t, 1H), 8.58 (d, 1H), 7.81 (dd, 1H),
7.49 (d, 1H), 7.36-7.39 (m, 2H), 7.32 (d, 2H), 7.12-7.14 (m, 2H),
7.02 (d, 2H), 6.84 (dd, 1H), 6.63 (dd, 1H), 6.37 (s, 1H), 6.13 (d,
1H), 4.44 (d, 2H), 4.30 (d, 2H), 3.55 (d, 2H), 3.01 (s, 4H), 2.70
(s, 2H), 2.11-2.15 (m, 7H), 1.93 (s 3H), 1.36 (t, 2H), 0.90 (s,
6H).
Example 265
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methoxycyclohexyl)amino]-3-nitropheny-
l}sulfonyl)benzamide
This example was prepared by substituting 4-methoxycyclohexanamine
for (3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in
EXAMPLE 187B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.16 (s, 2H), 8.83 (d, 1H), 8.30 (d, 1H), 7.79 (dd, 1H),
7.50 (d, 1H), 7.37-7.41 (m, 2H), 7.33 (d, 2H), 7.10-7.14 (m, 2H),
7.03 (d, 2H), 6.85 (dd, 1H), 6.65 (dd, 1H), 6.39 (s, 1H), 6.14 (d,
1H), 3.24-3.25 (m, 5H), 3.03 (s, 4H), 2.72 (s, 2H), 2.14-2.17 (m,
8H), 1.92 (m 3H), 1.63-1.65 (m, 2H), 1.38 (t, 2H), 0.92 (s,
6H).
Example 266
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[3-(1,1-dioxidothiomorpholin-4-yl)propyl]amino}-3-nitrophenyl-
)sulfonyl]-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 187A for
4-chloro-3-nitrobenzene sulfonamide and
4-(3-aminopropyl)thiomorpholine-1,1-dioxide for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.16 (s, 1H),
8.86 (t, 1H), 8.58 (d, 1H), 7.82 (dd, 1H), 7.50 (t, 1H), 7.40 (m,
2H), 7.33 (d, 2H), 7.15 (m, 1H), 7.04 (m, 3H), 6.85 (dd, 1H), 6.64
(m, 1H), 6.38 (m, 1H), 6.13 (m, 1H), 3.43 (m, 2H), 3.12 (m, 4H),
3.01 (m, 4H), 2.89 (m, 4H), 2.72 (m, 2H), 2.57 (t, 2H), 2.16 (m,
6H), 1.94 (m, 2H), 1.78 (t, 2H), 1.37 (t, 2H), 0.93 (s, 6H).
Example 267
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1
yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxopiperidin-1-yl)ethyl]am-
ino}phenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 187A for
4-chloro-3-nitrobenzene sulfonamide and
1-(2-aminoethyl)piperidine-2-one for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.12 (s, 1H),
8.61 (m, 1H), 8.52 (m, 1H), 7.78 (d, 1H), 7.51 (d, 1H), 7.37 (m,
2H), 7.33 (d, 2H), 7.10 (m, 2H), 7.04 (d, 2H), 6.81 (m, 1H), 6.61
(d, 1H), 6.37 (s, 1H), 6.13 (d, 1H), 3.52 (m, 4H), 3.28 (t, 2H),
3.00 (m, 4H), 2.71 (m, 2H), 2.17 (m, 8H), 1.94 (m, 2H), 1.63 (m,
4H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 268
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxoimidazolidin-1-yl)ethyl-
]amino}phenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 187A for
4-chloro-3-nitrobenzene sulfonamide and
1-(2-aminoethyl)-2-imidazolidone for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.17 (s, 1H),
8.60 (t, 1H), 8.56 (d, 1H), 7.81 (dd, 1H), 7.50 (m, 1H), 7.39 (m,
2H), 7.33 (d, 2H), 7.15 (m, 1H), 7.08 (d, 1H), 7.02 (d, 2H), 6.85
(dd, 1H), 6.65 (m, 1H), 6.39 (m, 2H), 6.15 (m, 1H), 3.51 (m, 2H),
3.39 (t, 2H), 3.30 (m, 2H), 3.21 (t, 2H), 3.03 (m, 4H), 2.72 (m,
2H), 2.14 (m, 6H), 1.93 (m, 2H), 1.37 (t, 2H), 0.92 (s, 6H).
Example 269
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-pyridin-4-ylethyl)amino]pheny-
l}sulfonyl)benzamide
This example was prepared by substituting 4-(2-aminoethyl)pyridine
for 1-(2-methoxyethyl)-piperidin-4-ylamine and EXAMPLE 187A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A, except the
material was purified by preparative HPLC on a Phenomenex Luna
C8(2) 5 um 100 .ANG. AXIA column (30 mm.times.75 mm). A gradient of
acetonitrile and 0.1% trifluoroacetic acid in water was used, at a
flow rate of 50 mL/minute (0-0.5 minutes 10% acetonitrile, 0.5-6.0
minutes linear gradient 10-100% acetonitrile, 6.0-7.0 minutes 100%
acetonitrile, 7.0-8.0 minutes linear gradient 100-10% acetonitrile)
to isolate the title compound as the bis trifluoroacetic acid salt.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.45 (br
s, 1H), 11.18 (br s, 1H), 8.77 (d, 2H), 8.61 (t, 1H), 8.60 (d, 1H),
7.86 (dd, 1H), 7.84 (d, 2H), 7.54 (d, 1H), 7.43-7.37 (m, 4H), 7.22
(d, 1H), 7.15 (d, 1H), 7.08 (d, 2H), 6.85 (dd, 1H), 6.70 (dd, 1H),
6.38 (t, 1H), 6.22 (d, 1H), 3.77 (q, 2H), 3.68-3.54 (m, 4H), 3.27
(m, 2H), 3.16 (t, 2H), 3.00 (m, 2H), 2.74 (m, 2H), 2.18 (m, 2H),
2.01 (d, 2H), 1.45 (t, 2H), 0.94 (s, 6H).
Example 270
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-morpholin-4-yl-3-nitrophenyl)sulfonyl]ben-
zamide
This example was prepared by substituting EXAMPLE 187A for
4-chloro-3-nitrobenzenesulfonamide and morpholine for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A, except the
crude material was purified by preparative HPLC using a C18 column,
250.times.50 mm, 10.mu., and eluting with a gradient of 20-100%
CH.sub.3CN vs. 0.1% trifluoroacetic acid in water, giving the title
compound as a trifluoroacetate salt. The salt was dissolved in
dichloromethane (6 mL) and was washed with 50% aqueous NaHCO.sub.3.
The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
filtered, and concentrated to give the title compound. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.17 (s, 1H), 8.31
(d, 1H), 7.87 (dd, 1H), 7.53 (d, 1H), 7.41 (m, 2H), 7.33 (d, 2H),
7.24 (d, 1H), 7.16 (s, 1H), 7.02 (d, 2H), 6.85 (dd, 1H), 6.64 (dd,
1H), 6.40 (s, 1H), 6.14 (s, 1H), 3.69 (t, 4H), 3.13 (t, 4H), 3.03
(br s, 4H), 2.75 (s, 2H), 2.19 (br s, 4H), 2.14 (br t, 2H), 1.95
(s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 271
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(4-methoxypiperidin-1-yl)-3-nitrophenyl]s-
ulfonyl}benzamide
This example was prepared by substituting EXAMPLE 187A for
4-chloro-3-nitrobenzenesulfonamide and 4-methoxy-piperidine for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A, except the
crude material was purified by preparative HPLC using a C18 column,
250.times.50 mm, 10.mu., and eluting with a gradient of 20-100%
CH.sub.3CN vs. 0.1% trifluoroacetic acid in water, giving the
product as a trifluoroacetate salt. The salt was dissolved in
dichloromethane (6 mL) and washed with 50% aqueous NaHCO.sub.3. The
organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered,
and concentrated to give the title compound. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) 611.17 (s, 1H), 8.28 (d, 1H), 7.81 (dd,
1H), 7.53 (d, 1H), 7.41 (m, 2H), 7.33 (d, 2H), 7.22 (d, 1H), 7.16
(s, 1H), 7.04 (d, 2H), 6.86 (dd, 1H), 6.64 (dd, 1H), 6.40 (s, 1H),
6.14 (s, 1H), 3.42 (m, 1H), 3.27 (s, 3H), 3.25 (m, 2H), 3.00 (m,
6H), 2.73 (s, 2H), 2.18 (br s, 4H), 2.13 (br t, 2H), 1.94 (s, 2H),
1.91 (m, 2H), 1.56 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 272
4-(4-{[2-(4-chlorophenyl)-5-pyrrolidin-1-ylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylme-
thyl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting pyrrolidine for
morpholine in EXAMPLE 249G. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.04 (s, 1H), 8.44 (d, 1H),
8.42 (m, 1H), 7.70 (dd, 1H), 7.55 (d, 1H), 7.37 (d, 2H), 7.32 (m,
2H), 7.09 (d, 2H), 7.00 (d, 1H), 6.89 (d, 1H), 6.76 (d, 1H), 6.54
(d, 1H), 6.32 (d, 1H), 6.13 (d, 1H), 3.83 (m, 3H), 3.06 (m, 15H),
2.23 (m, 6H), 1.84 (m, 6H), 1.62 (m, 4H), 1.24 (m, 3H).
Example 273
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]am-
ino}phenyl)sulfonyl]benzamide
Example 273A
3-nitro-4-[2-(3-oxo-piperazin-1-yl)-ethylamino]-benzenesulfonamide
4-(2-Amino-ethyl)-piperazin-2-one (5.51 g) and triethylamine (9.07
mL, 6.59 g) were added to 1,4-dioxane (100 mL),
N,N-dimethylacetamide (20 mL), and water (10 mL) and mixed until
dissolved. 4-Chloro-3-nitrobenzenesulfonamide (7.00 g) was added,
and the mixture was heated to 90.degree. C. for 16 hours. The
mixture was cooled and the solvent was removed under vacuum. The
crude material was purified by recrystallization from 20% methanol
in dichloromethane with subsequent washing of the recrystallized
solid with 10% methanol in dichloromethane followed by washing with
100% dichloromethane.
Example 273B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]am-
ino}phenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 273A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.15 (br s, 1H), 8.73 (t,
1H), 8.58 (d, 1H), 7.82 (dd, 1H), 7.76 (br s, 1H), 7.51 (d, 1H),
7.42-7.38 (m, 2H), 7.34 (d, 2H), 7.16 (d, 1H), 7.06-7.01 (m, 3H),
6.85 (dd, 1H), 6.65 (dd, 1H), 6.38 (t, 1H), 6.15 (d, 1H), 3.48 (q,
2H), 3.17 (m, 2H), 3.04 (m, 6H), 2.72 (br s, 2H), 2.70-2.62 (m,
2H), 2.16 (m, 8H), 1.95 (br s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 274
4-[4-({4'-chloro-4-[2-(dimethylamino)ethoxy]-1,1'-biphenyl-2-yl}methyl)pip-
erazin-1-yl]-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 125D for EXAMPLE
26C and EXAMPLE 174A for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.62 (s, 1H), 11.33
(s, 1H), 9.55 (d, 1H), 8.49 (d, 1H), 7.74 (dd, 1H), 7.55 (m, 5H),
7.35 (m, 2H), 7.30 (m, 1H), 7.19 (dd, 2H), 6.96 (m, 2H), 6.73 (dd,
1H), 6.40 (m, 1H), 6.33 (m, 1H), 6.24 (s, 1H), 4.37 (m, 2H), 3.53
(m, 8H), 3.30 (m, 8H), 3.23 (m, 4H), 2.90 (s, 6H), 2.84 (s,
3H).
Example 275
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}-3-nitrophenyl-
)sulfonyl]-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 187A for
4-chloro-3-nitrobenzene sulfonamide and
(1,1-dioxidotetrahydrothien-3-yl)methylamine hydrochloride for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.17 (s, 1H),
8.72 (t, 1H), 8.59 (d, 1H), 7.82 (dd, 1H), 7.51 (d, 1H), 7.40 (m,
2H), 7.33 (d, 2H), 7.16 (m, 2H), 7.03 (d, 2H), 6.86 (dd, 1H), 6.65
(dd, 1H), 6.40 (m, 1H), 6.14 (d, 1H), 3.55 (t, 2H), 3.28 (m, 1H),
3.23 (m, 1H), 3.05 (m, 5H), 2.91 (m, 1H), 2.74 (m, 3H), 2.27 (m,
1H), 2.15 (m, 6H), 1.95 (m, 2H), 1.86 (m, 1H), 1.38 (t, 2H), 0.91
(s, 6H).
Example 276
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-3-nitrophenyl}sulfony-
l)-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 187A for
4-chloro-3-nitrobenzene sulfonamide and
1,1-dioxidotetrahydrothiene-3ylamine for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.20 (bs, 1H),
11.15 (s, 1H), 8.59 (d, 1H), 8.50 (d, 1H), 7.86 (dd, 1H), 7.50 (d,
1H), 7.39 (m, 2H), 7.33 (d, 2H), 7.19 (d, 1H), 7.14 (m, 1H), 7.03
(d, 2H), 6.85 (dd, 1H), 6.65 (dd, 1H), 6.39 (m, 1H), 6.15 (d, 1H),
4.63 (m, 1H), 3.64 (m, 1H), 3.37 (m, 2H), 3.20 (m, 1H), 3.03 (m,
4H), 2.73 (m, 2H), 2.57 (m, 1H), 2.28 (m, 1H), 2.15 (m, 6H), 1.95
(m, 2H), 1.38 (t, 2H), 0.91 (s, 6H).
Example 277
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-
-(trifluoromethyl)phenyl]sulfonyl}benzamide
Example 277A
4-((tetrahydro-2H-pyran-4-yl)methylamino)-3-(trifluoromethyl)benzenesulfon-
amide
A mixture of 4-fluoro-3-(trifluoromethyl)benzenesulfonamide (1.056
g), (tetrahydro-2H-pyran-4-yl)methanamine (0.5 g) and
N,N-diisopropylethylamine (1.68 g) in anhydrous dimethylsulfoxide
(15 mL) solution was heated at 90.degree. C. overnight. The
reaction mixture was cooled to room temperature and diluted with
ethyl acetate. The organic phase was washed with water, brine,
dried over anhydrous sodium sulfate, filtered and concentrated to
afford the title compound.
Example 277B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-
-(trifluoromethyl)phenyl]sulfonyl}benzamide
This example was prepared by substituting EXAMPLE 277A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.22 (s, 1H), 11.20 (s, 1H), 7.91 (d, 1H), 7.76 (dd, 1H),
7.55 (d, 1H). 7.41 (m, 4H), 7.20 (m, 1H) 7.08 (d, 2H), 6.88 (m,
2H), 6.70 (dd, 1H), 6.58 (m, 1H), 6.42 (m, 1H), 6.19 (m, 1H), 3.83
(m, 2H), 3.56 (m, 4H), 3.25 (m, 4H), 3.15 (m, 2H), 2.99 (m, 2H),
2.74 (m, 2H), 2.18 (m, 2H), 2.02 (m, 2H), 1.84 (m, 1H), 1.57 (m,
2H), 1.44 (m, 2H), 1.19 (m, 2H), 0.93 (s, 6H).
Example 278
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[2-(1,3-dioxolan-2-yl)ethyl]-3-nitrophenyl}sulfonyl)-2-(1H-ind-
ol-5-yloxy)benzamide
A mixture of EXAMPLE 187A (0.079 g),
dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (0.016 g), and
palladium acetate (0.0045 g) in tetrahydrofuran (1 mL) was stirred
at room temperature for 5 minutes. To this mixture was added
(2-(1,3-dioxolan-2-yl)ethyl)zinc(II) bromide (0.6 mL). The reaction
mixture was stirred overnight. The solvent was removed, and the
residue was purified by reverse phase Prep HPLC. The desired
fractions were combined, and the organic solvent was partially
removed. The resulting mixture was treated with saturated aqueous
NaHCO.sub.3, extracted with ethyl acetate, dried over MgSO.sub.4,
filtered, and concentrated to give the title compound. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.14 (s, 1H), 8.37
(s, 1H), 8.00 (s, 1H), 7.55 (br s., 1H), 7.52 (d, 1H), 7.33-7.39
(m, 4H), 7.08 (br s, 1H), 7.04 (d, 2H), 6.83 (dd, 1H), 6.62 (d,
1H), 6.38 (s, 1H), 6.15 (d, 1H), 4.85 (t, 1H), 3.87-3.89 (m, 2H),
3.76-3.79 (m, 2H), 3.04 (s, 4H), 2.91-2.94 (m, 2H), 2.11-2.15 (m,
4H), 1.88-1.91 (s, 4H), 1.39 (t, 2H), 0.92 (s, 6H).
Example 279
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)-
phenyl]sulfonyl}benzamide
Example 279A
3-nitro-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide
(Tetrahydro-2H-pyran-4-yl)methanol (2.0 g) in tetrahydrofuran (20
mL) was treated with 60% NaH (1.377 g). The mixture was stirred for
20 minutes at the room temperature. To this mixture was added
4-fluoro-3-nitrobenzenesulfonamide (2.84 g) portionwise. The
reaction was stirred for another 2 hours. The mixture was poured
into water, neutralized with 10% HCl, and extracted with ethyl
acetate three times. The combined organic layers were washed with
brine, dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified with flash column chromatography on silica gel
eluting with 20%-60% ethyl acetate in hexanes.
Example 279B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)-
phenyl]sulfonyl}benzamide
This example was prepared by substituting EXAMPLE 279A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.16 (s, 1H), 8.38 (d, 1H), 8.05 (dd, 1H), 7.51 (d, 1H),
7.38-7.41 (m, 3H), 7.34 (d, 1H), 7.15 (d, 1H), 7.04 (d, 2H), 6.85
(dd, 1H), 6.65 (dd, 1H), 6.39 (s, 1H), 6.15 (d, 1H), 4.08 (d, 2H),
3.88 (dd, 2H), 3.04 (s, 4H), 2.77 (s, 2H), 2.12-2.22 (m, 4H), 1.95
(br s, 2H), 1.64 (dd, 2H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).
Example 280
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]am-
ino}phenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 273A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.24 (br s, 1H), 8.72 (t,
1H), 8.51 (d, 1H), 7.76 (br s, 1H), 7.72 (dd, 1H), 7.53 (d, 1H),
7.34 (d, 2H), 7.28 (t, 1H), 7.18 (d, 1H), 7.04 (d, 2H), 6.97 (t,
2H), 6.70 (dd, 1H), 6.43 (d, 1H), 6.28-6.23 (m, 2H), 3.48 (q, 2H),
3.17 (m, 2H), 3.04 (m, 6H), 2.70 (br s, 2H), 2.68-2.63 (m, 2H),
2.16 (m, 8H), 1.95 (br s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 281
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methyl-5-oxopyrrolidin-3-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 187A for
4-chloro-3-nitrobenzenesulfonamide and
4-amino-1-methylpyrrolidin-2-one hydrochloride for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A, except the
crude was purified by preparative HPLC using a C18 column,
250.times.50 mm, 10.mu., and eluting with a gradient of 20-100%
CH.sub.3CN vs. 0.1% trifluoroacetic acid in water, giving the
product as a trifluoroacetate salt. The salt was dissolved in
dichloromethane (6 mL) and washed with 50% aqueous NaHCO.sub.3. The
organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered,
and concentrated to give the title compound. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.14 (s, 1H), 8.56 (d, 1H),
8.34 (br d, 1H), 7.82 (dd, 1H), 7.53 (d, 1H), 7.39 (m, 2H), 7.33
(d, 2H), 7.11 (s, 1H), 7.04 (m, 3H), 6.83 (dd, 1H), 6.64 (dd, 1H),
6.38 (s, 1H), 6.15 (s, 1H), 4.45 (m, 1H), 3.80 (dd, 1H), 3.35 (m,
1H), 3.02 (br s, 4H), 2.81 (dd, 1H), 2.75 (s, 3H), 2.71 (s, 2H),
2.40 (dd, 1H), 2.15 (m, 6H), 1.94 (s, 2H), 1.38 (t, 2H), 0.92 (s,
6H).
Example 282
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methyl-6-oxopiperidin-3-yl)amino]-3-n-
itrophenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 187A for
4-chloro-3-nitrobenzenesulfonamide and
5-amino-1-methylpiperidin-2-one hydrochloride for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A, except the
crude was purified by preparative HPLC using a C18 column,
250.times.50 mm, 10 t, and eluting with a gradient of 20-100%
CH.sub.3CN vs. 0.1% trifluoroacetic acid in water, giving the
product as a trifluoroacetate salt. The salt was dissolved in
dichloromethane (6 mL) and washed with 50% aqueous NaHCO.sub.3. The
organic layer was dried over anhydrous Na.sub.2SO.sub.4 and
concentrated to give the title compound. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.16 (s, 1H), 8.58 (d, 1H),
8.31 (br d, 1H), 7.85 (dd, 1H), 7.53 (d, 1H), 7.39 (m, 2H), 7.33
(d, 2H), 7.25 (d, 1H), 7.14 (s, 1H), 7.03 (d, 2H), 6.85 (dd, 1H),
6.64 (dd, 1H), 6.39 (s, 1H), 6.14 (s, 1H), 4.22 (m, 1H), 3.57 (dd,
1H), 3.02 (br s, 4H), 2.84 (m, 1H), 2.83 (s, 3H), 2.72 (s, 2H),
2.36 (m, 2H), 2.16 (m, 6H), 2.05 (m, 2H), 1.94 (s, 2H), 1.38 (t,
2H), 0.92 (s, 6H).
Example 283
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-{[.sup.3-nitro-4-(piperidin-1-ylamino)phenyl]-
sulfonyl}benzamide
Example 283A
3-nitro-4-(piperidin-1-ylamino)benzenesulfonamide
This example was prepared by substituting piperidin-1-amine for
(tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 1F.
Example 283B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulfo-
nyl}benzamide
This example was prepared by substituting EXAMPLE 283A for EXAMPLE
1F and EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.27 (brs, 1H), 11.33 (s,
1H), 9.14 (s, 1H), 8.48 (d, 1H), 7.66 (dd, 1H), 7.52 (t, 2H), 7.34
(d, 2H), 7.29 (t, 1H), 7.19 (d, 1H), 7.04 (d, 2H), 6.97 (t, 1H),
6.71 (dd, 1H), 6.41 (d, 1H), 6.28 (m, 2H), 3.05 (m, 4H), 2.78 (m,
6H), 2.17 (m, 6H), 1.95 (s, 2H), 1.67 (m, 6H), 1.38 (t, 2H), 0.93
(s, 6H).
Example 284
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulfo-
nyl}benzamide
This example was prepared by substituting EXAMPLE 283A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.28 (s, 1H), 11.11 (s, 1H), 9.02 (s, 1H), 8.50 (s, 1H),
7.79 (dd, 1H), 7.52 (m, 2H), 7.35 (m, 4H), 7.07 (m, 3H), 6.82 (m,
1H), 6.60 (m, 1H), 6.36 (m, 1H), 6.14 (m, 1H), 2.99 (m, 4H), 2.75
(m, 6H), 2.16 (m, 6H), 1.99 (m, 2H), 1.94 (m, 2H), 1.64 (m, 4H),
1.38 (t, 2H), 0.92 (s, 6H).
Example 285
4-(4-{[4-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl]methyl}piperazin-1-yl)--
2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-
phenyl}sulfonyl)benzamide
Example 285A
4-(4-chlorophenyl)-1-methyl-1H-pyrazole-5-carbaldehyde
4-Bromo-1-methyl-1H-pyrazole-5-carbaldehyde (0.500 g),
4-chlorophenylboronic acid (0.455 g), tetrabutylammonium bromide
(0.853 g), potassium carbonate (0.914 g) and palladium acetate
(0.030 g) were stirred together in 5 mL of water and heated to
45.degree. C. After stirring for 2.5 hours, the reaction was
diluted with ethyl acetate (75 mL) and washed with water (25 mL),
brine (50 mL), dried over magnesium sulfate, filtered and
concentrated to give the crude material. The solid was
chromatographed over silica gel (SF40-80) eluted using a gradient
of 5% to 25% ethyl acetate/hexanes over 30 minutes.
Example 285B
methyl
2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-1-methyl-1H-pyrazol--
5-yl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 285A for
4'-chlorobiphenyl-2 carboxaldehyde and methyl
2-(1H-indol-5-yloxy)-4-(piperazin-1-yl)benzoate for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 285C
2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl)me-
thyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 285B for EXAMPLE
1D in EXAMPLE 1E.
Example 285D
2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl)me-
thyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)p-
henylsulfonyl)benzamide
This example was prepared by substituting EXAMPLE 285C for EXAMPLE
1E in EXAMPLE 1G. .sup.1H NMR (300 MHz, CDCL3) .delta. 10.30 (s,
1H), 8.85 (d, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 8.12 (dd, 1H), 7.95
(d, 1H), 7.49 (s, 1H), 7.43 (d, 1H), 7.36-7.22 (m, 6H), 6.97 (dd,
1H), 6.87 (d, 1H), 6.53 (d, 2H), 6.08 (s, 1H), 4.08-3.98 (m, 2H),
3.92 (s, 3H), 3.55 (s, 2H), 3.42 (s, 2H), 3.33-3.19 (m, 2H), 3.08
(s, 4H), 2.38 (s, 4H), 1.98 (d, 1H), 1.72 (s, 2H), 1.52-1.33 (m,
2H).
Example 286
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methyloxetan-3-yl)methoxy]-3-nitrophe-
nyl}sulfonyl)benzamide
Example 286A
4-((3-methyloxetan-3-yl)methoxy)-3-nitrobenzenesulfonamide
This example was prepared by substituting
(3-methyloxetan-3-yl)methanol for
(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 279A.
Example 286B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methyloxetan-3-yl)methoxy]-3-nitrophe-
nyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 286A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.08 (s, 1H), 8.26 (d, 1H), 8.18 (d, 1H), 7.92 (m, 1H),
7.53 (m, 1H), 7.34 (m, 3H), 7.25 (m, 1H), 7.04 (m, 3H), 6.91 (m,
1H), 6.76 (m, 1H), 6.59 (m, 1H), 6.35 (m, 1H), 6.15 (d, 1H), 4.47
(d, 1H), 4.29 (d, 1H), 3.40 (m, 2H), 3.13 (m, 2H), 2.98 (m, 4H),
2.72 (m, 2H), 2.16 (m, 6H), 1.94 (m, 2H), 1.36 (m, 5H), 0.93 (s,
6H).
Example 287
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(H-indol-5-yloxy)-N-[(3-nitro-4-{[(1-oxidotetrahydro-2H-thiopyran--
4-yl)methyl]amino}phenyl)sulfonyl]benzamide
Example 287A
3-nitro-4-((tetrahydro-2H-thiopyran-4-yl)methylamino)benzenesulfonamide
This example was prepared by substituting
(tetrahydro-2H-thiopyran-4-yl)methanamine, hydrochloride for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 287B
3-nitro-4-((1-oxidotetrahydro-2H-thiopyran-4-yl)methylamino)benzenesulfona-
mide
EXAMPLE 287A (150 mg) was suspended in methanol (5 mL). The
reaction mixture was cooled to 0.degree. C., followed by the
addition of Oxone.RTM. (220 mg) in water (3 mL).
The reaction mixture was stirred at room temperature for 2 hours.
The precipitate was filtered and washed with Na.sub.2S.sub.2O.sub.3
solution and water. The solid was dried in a vacuum oven overnight,
and used in the next step without further purification.
Example 287C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1-oxidotetrahydro-2H-thiopyran-
-4-yl)methyl]amino}phenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 287B for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.17 (s, 1H). 8.69 (t, 1H), 8.58 (d, 1H), 7.81 (dd, 1H),
7.51 (d, 1H), 7.40 (m, 2H), 7.33 (d, 2H), 7.15 (m, 2H), 7.03 (d,
2H), 6.86 (dd, 1H), 6.65 (dd, 1H), 6.40 (m, 1H), 6.13 (m, 1H), 3.38
(m, 4H), 3.05 (m, 6H), 2.73 (m, 2H), 2.11 (m, 8H), 1.95 (m, 3H),
1.67 (m, 2H), 1.38 (t, 2H), 0.90 (s, 6H).
Example 288
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1,3-thiazol-5-ylmethyl)amino]ph-
enyl}sulfonyl)benzamide
This example was prepared by substituting thiazol-5-ylmethanamine,
hydrochloric acid for (3S,4R)-4-amino-1-benzylpiperidin-3-ol,
hydrochloric acid in EXAMPLE 187B. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.18 (s, 2H), 9.13 (t, 1H),
8.99 (s, 1H), 8.60 (d, 1H), 7.95 (s, 1H), 7.82 (dd, 1H), 7.50 (d,
1H), 7.39-7.42 (, 2H), 7.33 (d, 2H), 7.17 (d, 1H), 7.14 (d, 1H),
7.03 (d, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.40 (s, 1H), 6.13 (d,
1H), 4.91 (d, 2H), 3.03 (s, 4H), 2.73 (s, 2H), 2.12-2.18 (m, 6H),
1.94 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 289
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)-
phenyl]sulfonyl}benzamide
This example was prepared by substituting EXAMPLE 279A for EXAMPLE
1F and EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.25 (s, 1H), 8.21 (d,
J=2.14 Hz, 1H), 7.95 (dd, 1H), 7.54 (d, 1H), 7.33-7.38 (m, 3H),
7.28 (t, 1H), 7.17 (d, 1H), 7.04 (d, 2H), 6.97 (t, 1H), 6.70 (dd,
1H), 6.41 (d, 1H), 6.27-6.29 (m, 2H), 4.08 (d, 2H), 3.88 (dd, 2H),
3.07 (s, 4H), 2.80 (s, 2H), 2.24 (br s, 2H), 2.12-2.16 (m, 2H),
1.96 (s, 2H), 1.65 (dd, 2H), 1.37-1.40 (m, 2H), 0.92 (s, 6H).
Example 290
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)-
amino]phenyl}sulfonyl)benzamide
Example 290A
2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enecarbaldehyde
The title compound was prepared as described in EXAMPLE 253B by
replacing EXAMPLE 253A with EXAMPLE 19C.
Example 290B
tert-butyl
4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piper-
azine-1-carboxylate
The title compound was prepared as described in EXAMPLE 1A by
replacing EXAMPLE 27C with EXAMPLE 290A.
Example 290C
1-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazine
The title compound was prepared as described in EXAMPLE 1B by
replacing EXAMPLE 1A with EXAMPLE 290B.
Example 290D
ethyl
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex--
1-enyl)methyl)piperazin-1-yl)benzoate
The title compound was prepared as described in EXAMPLE 20D by
replacing EXAMPLE 20A and EXAMPLE 20C with EXAMPLE 26A and EXAMPLE
290C, respectively.
Example 290E
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl-
)methyl)piperazin-1-yl)benzoic acid
The title compound was prepared as described in EXAMPLE 1E by
replacing EXAMPLE 1D with EXAMPLE 290D.
Example 290F
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl-
)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamin-
o)phenylsulfonyl)benzamide
The title compound was prepared as described in EXAMPLE 175F by
replacing EXAMPLE 175E with EXAMPLE 290E. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.17 (s, 2H), 8.62 (t, 1H),
8.58 (d, 1H), 7.80 (dd, 1H), 7.51 (d, 1H), 7.38-7.43 (m, 2H), 7.33
(d, 2H), 7.16 (d, 1H), 7.10 (d. 1H), 7.07 (d, 3H), 6.86 (dd, 1H),
6.65 (dd, 1H), 6.39 (s, 1H), 6.14 (d, 1H), 3.85 (dd, 2H), 3.23-3.31
(m, 4H), 3.02 (s, 4H), 2.68 (s, 2H), 2.17 (d, 6H), 1.85-1.95 (m,
3H), 1.61 (d, 2H), 1.39 (t, 2H), 1.20-1.30 (m, 2H), 0.92 (s,
6H).
Example 291
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-tetrahydro-2H-pyran-4-ylethyl-
)amino]phenyl}sulfonyl)benzamide
Example 291A
3-nitro-4-(2-(tetrahydro-2H-pyran-4-yl)ethylamino)benzenesulfonamide
The title compound was prepared as described in EXAMPLE 1F by
replacing (tetrahydropyran-4-yl)methylamine with
2-(tetrahydro-2H-pyran-4-yl)ethanamine.
Example 291B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-tetrahydro-2H-pyran-4-ylethyl-
)amino]phenyl}sulfonyl)benzamide
The title compound was prepared as described in EXAMPLE 175F by
replacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE
291A, respectively. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.16 (s, 2H), 8.57 (d, 1H),
8.53 (t, 1H), 7.80 (dd, 1H), 7.51 (d, 1H), 7.37-7.42 (m, 2H), 7.33
(d, 2H), 7.14 (d, 1H), 7.01-7.05 (m, 3H), 6.85 (dd, 1H), 6.64 (dd,
1H), 6.39 (s, 1H), 6.14 (d, 1H), 3.83 (dd, 2H), 3.41 (q, 2H),
3.23-3.30 (m, 2H), 3.02 (s, 4H), 2.71 (s, 2H), 2.08-2.21 (m, 6H),
1.94 (s, 2H), 1.52-1.67 (m, 5H), 1.37 (t, 2H), 1.14-1.25 (m, 2H),
0.92 (s, 6H).
Example 292
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amino-
}phenyl)sulfonyl]benzamide
Example 292A
3-nitro-4-(2-(trifluoromethoxy)ethylamino)benzenesulfonamide
This example was prepared by substituting piperidin-1-amine for
(tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 1F.
Example 292B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amino-
}phenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 292A for EXAMPLE
1F and EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.07 (s, 1H), 8.36 (m,
2H), 7.72 (dd, 1H), 7.58 (d, 1H), 7.34 (d, 2H), 7.19 (m, 1H), 7.05
(m, 3H), 6.91 (m, 2H), 6.59 (d, 1H), 6.21 (m, 3H), 4.28 (t, 2H),
3.72 (q, 2H), 2.94 (m, 4H), 2.71 (s, 2H), 2.15 (m, 6H), 1.95 (s,
2H), 1.39 (t, 2H), 0.93 (s, 6H).
Example 293
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitro-
phenyl)sulfonyl]benzamide
Example 293A
4-(2-(2-methoxyethoxy)ethylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting
2-(2-methoxyethoxy)ethanamine for
(tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 1F.
Example 293B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitro-
phenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 293A for EXAMPLE
1F and EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.28 (s, 1H), 11.23 (s,
1H), 8.59 (m, 1H), 8.50 (d, 1H), 7.70 (dd, 1H), 7.52 (d, 1H), 7.34
(d, 2H), 7.28 (t, 1H), 7.17 (d, 1H), 7.05 (m, 3H), 6.96 (t, 1H),
6.71 (dd, 1H), 6.42 (d, 1H), 6.26 (m, 2H), 3.67 (t, 2H), 3.56 (m,
4H), 3.45 (m, 2H), 3.22 (s, 3H), 3.04 (m, 4H), 2.74 (s, 2H), 2.16
(m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.93 (s, 6H).
Example 294
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[3-(methylsulfonyl)propyl]amino}-3-nitro-
phenyl)sulfonyl]benzamide
Example 294A
4-(3-(methylthio)propylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting
3-(methylthio)propan-1-amine for (tetrahydropyran-4-yl)methylamine
in EXAMPLE 1F.
Example 294B
4-(3-(methylsulfonyl)propylamino)-3-nitrobenzenesulfonamide
EXAMPLE 294A (150 mg) was suspended in anhydrous dichloromethane (5
mL) and meta-chloroperoxybenzoic acid (848 mg) was added at
0.degree. C. The reaction mixture was stirred at room temperature
overnight. The cloudy suspension was filtered. The solid was washed
with aqueous Na.sub.2S.sub.2O.sub.3 solution, saturated aqueous
NaHCO.sub.3 solution and water.
The solid was dried and used in the next step without further
purification.
Example 294C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[3-(methylsulfonyl)propyl]amino}-3-nitro-
phenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
26C and EXAMPLE 294B for EXAMPLE 1F in EXAMPLE 177.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.25 (m, 1H), 8.65 (t, 1H),
8.51 (d, 1H), 7.69 (dd, 1H), 7.52 (d, 1H), 7.34 (d, 2H), 7.28 (m,
1H), 7.18 (m, 1H), 7.05 (m, 3H), 6.97 (m, 1H), 6.70 (dd, 1H), 6.42
(d, 1H), 6.26 (m, 2H), 3.55 (m, 2H), 3.23 (t, 2H), 3.05 (t, 4H),
2.98 (s, 3H), 2.76 (m, 2H), 2.18 (m, 6H), 2.02 (m, 2H), 1.96 (m,
2H), 1.38 (t, 2H), 0.93 (s, 6H).
Example 295
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[3-(1-dioxidothiomorpholin-4-yl)propyl]amino}-3-nitrophenyl)s-
ulfonyl]-2-(1H-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 337A for
4-chloro-3-nitrobenzene sulfonamide and
4-(3-aminopropyl)thiomorpholine-1,1-dioxide for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.23 (s, 1H),
8.79 (s, 1H), 8.48 (d, 1H), 7.72 (dd, 1H), 7.54 (d, 1H), 7.34 (d,
2H), 7.26 (t, 1H), 7.15 (d, 1H), 6.99 (m, 4H), 6.67 (dd, 1H), 6.40
(d, 1H), 6.24 (m, 2H), 3.42 (q, 2H), 3.11 (m, 4H), 3.01 (m, 4H),
2.90 (m, 4H), 2.72 (m, 2H), 2.56 (t, 2H), 2.16 (m, 6H), 1.95 (m,
2H), 1.78 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 296
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethyl)-
phenyl]sulfonyl}benzamide
Example 296A
(2-(tetrahydro-2H-pyran-4-yl)ethyl)zinc(II) bromide
A 25 mL round bottom flask was dried at 120.degree. C. for 6 hours.
It was cooled by a stream of dry N.sub.2. To this flask was charged
with zinc (0.508 g). The flask was heated at 70.degree. C. under
high vacuum for 30 minutes. After back-filling with N.sub.2, iodine
(0.033 g) and N,N-dimethylacetamide (5.2 mL) were added, and the
resulting mixture was stirred until the red color of iodine had
faded. Then, 4-(2-bromoethyl)tetrahydro-2H-pyran (1.0 g) was added
to the above mixture via a syringe. The reaction mixture was
allowed to stir for 12 hours at 70.degree. C. After cooling, the
reaction mixture was used directly for next step.
Example 296B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethyl)-
phenyl]sulfonyl}benzamide
This example was prepared by substituting EXAMPLE 296A for
(2-(1,3-dioxolan-2-yl)ethyl)zinc(II) bromide in EXAMPLE 278.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.15 (s,
2H), 8.38 (d, 1H), 8.01 (d, 1H), 7.57 (d, 1H), 7.51 (d, 1H),
7.38-7.40 (m, 2H), 7.34 (d, 2H), 7.12 (d, 1H), 7.04 (d, 2H), 6.82
(dd, 1H), 6.64 (dd, 1H), 6.38 (s, 1H), 6.16 (d, 1H), 3.83 (dd, 2H),
3.24-3.29 (m, 4H), 3.06 (s, 4H), 2.83-2.86 (m, 3H), 2.27 (br s,
2H), 2.12-2.14 (m, 4H), 1.96 (s, 2H), 1.95 (s, 2H), 1.46-1.62 (m,
6H), 1.37-1.40 (m, 2H), 0.92 (s, 6H).
Example 297
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-
-yloxy)benzamide
Example 297A
4-((1,4-dioxan-2-yl)methoxy)-3-nitrobenzenesulfonamide
(1,4-Dioxan-2-yl)methanol (380 mg) in tetrahydrofuran (30 ml) was
treated with sodium hydride (60%) (245 mg) at room temperature for
30 minutes. The reaction mixture was cooled in an ice bath and
4-fluoro-3-nitrobenzenesulfonamide (675 mg) was added. The
resulting mixture was stirred at room temperature for 2 hours and
another portion of sodium hydride (60%, 245 mg) was added. The
reaction mixture was stirred overnight and quenched with ice water
(3 ml). The cloudy mixture was filtered and the filtrate was
concentrated. The residue was triturated with methanol to give the
title compound.
Example 297B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-
-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 175F by
replacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE
297A, respectively. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.16 (s, 2H), 8.39 (d, 1H),
8.06 (dd, 1H), 7.51 (d, 1H), 7.38-7.43 (m, 3H), 7.34 (d, 2H), 7.15
(d, 1H), 7.04 (d, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.39 (s, 1H),
6.15 (d, 1H), 4.20-4.28 (m, 2H), 3.85-3.91 (m, 1H), 3.82 (dd, 1H),
3.74-3.78 (m, 1H), 3.59-3.69 (m, 2H), 3.40-3.51 (m, 2H), 3.05 (s,
4H), 2.78 (s, 2H), 2.23 (s, 4H), 2.14 (s, 2H), 1.95 (s, 2H), 1.38
(t, 2H), 0.92 (s, 6H).
Example 298
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitro-
phenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 293A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.17 (s, 1H), 11.15 (s, 1H), 8.59 (m, 2H), 7.80 (dd, 1H),
7.50 (d, 1H), 7.36 (m, 4H), 7.15 (d, 1H), 7.09 (d, 1H), 7.03 (d,
2H), 6.85 (dd, 1H), 6.65 (dd, 1H), 6.39 (m, 1H), 6.14 (d, 1H), 3.67
(t, 2H), 3.56 (m, 4H), 3.44 (m, 2H), 3.22 (s, 3H), 3.03 (m, 4H),
2.72 (s, 2H), 2.16 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s,
6H).
Example 299
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-3-nitrophenyl}sulfony-
l)-2-(1H-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 337A for
4-chloro-3-nitrobenzene sulfonamide and
1,1-dioxidotetrahydrothiene-3ylamine for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.35 (s, 1H),
11.23 (s, 1H), 8.49 (m, 2H), 7.78 (dd, 1H), 7.52 (d, 1H), 7.34 (d,
2H), 7.27 (m, 1H), 7.16 (m, 2H), 7.04 (d, 1H), 6.97 (m, 1H), 6.70
(dd, 1H), 6.42 (d, 1H), 6.26 (m, 2H), 4.63 (m, 1H), 3.64 (dd, 1H),
3.37 (m, 2H), 3.20 (m, 1H), 3.05 (m, 4H), 2.74 (m, 2H), 2.58 (m,
1H), 2.28 (m, 1H), 2.16 (m, 6H), 1.95 (m, 2H), 1.38 (t, 2H), 0.92
(s, 6H).
Example 300
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amino-
}phenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 292A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.17 (m, 2H), 8.64 (t, 1H), 8.59 (d, 1H), 7.84 (dd, 1H),
7.51 (d, 1H), 7.40 (m, 2H), 7.33 (d, 2H), 7.16 (m, 2H), 7.04 (d,
2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.39 (m, 1H), 6.14 (d, 1H), 4.31
(t, 2H), 3.78 (q, 2H), 3.04 (m, 4H), 2.74 (s, 2H), 2.17 (m, 6H),
1.94 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 301
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}-3-nit-
rophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide
Example 301A
3-nitro-4-((1-dioxidotetrahydro-2H-thiopyran-4-yl)methylamino)benzenesulfo-
namide
This example was prepared by substituting EXAMPLE 287A for EXAMPLE
294A in EXAMPLE 294B.
Example 301B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}-3-nit-
rophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
26C and EXAMPLE 301A for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.26 (s, 1H), 8.68
(t, 1H), 8.51 (d, 1H), 7.73 (dd, 1H), 7.53 (d, 1H), 7.34 (d, 2H),
7.29 (m, 1H), 7.19 (d, 1H), 7.12 (d, 1H), 7.04 (d, 2H), 6.99 (m,
1H), 6.70 (dd, 1H), 6.46 (d, 1H), 6.26 (m, 2H), 3.38 (t, 2H), 3.09
(m, 8H), 2.75 (m, 2H), 2.16 (m, 6H), 2.07 (m, 2H), 1.95 (m, 3H),
1.70 (m, 2H), 1.38 (t, 2H), 0.91 (s, 6H).
Example 302
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2,2-difluoroethyl)amino]-3-nitrophenyl}sulfonyl)-2-(H-indol--
5-yloxy)benzamide
Example 302A
4-(2,2-difluoroethylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting 2,2-difluoroethanamine
for (tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 1F.
Example 302B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2,2-difluoroethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-
-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 302A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.22 (s, 1H), 11.05 (s, 1H), 8.46 (m, 2H), 7.76 (m, 1H),
7.53 (d, 1H), 7.33 (m, 4H), 7.05 (m, 4H), 6.76 (m, 1H), 6.57 (d,
1H), 6.34 (m, 1H), 6.14 (m, 1H), 3.89 (m, 2H), 2.97 (m, 4H), 2.71
(s, 2H), 2.16 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s,
6H).
Example 303
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-
-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
26C and EXAMPLE 163A for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.28 (m, 1H), 8.13
(d, 1H), 7.78 (dd, 1H), 7.52 (d, 1H), 7.34 (d, 2H), 7.29 (m, 2H),
7.20 (d, 1H), 7.01 (m, 4H), 6.70 (dd, 1H), 6.45 (d, 1H), 6.27 (m,
2H), 3.85 (dd, 2H), 3.26 (t, 4H), 3.05 (m, 4H), 2.75 (m, 2H), 2.16
(m, 6H), 1.95 (m, 2H), 1.84 (m, 1H), 1.55 (m, 2H), 1.38 (t, 2H),
1.23 (m, 2H), 0.92 (s, 6H).
Example 304
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-
-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 163A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.46 (s, 1H), 11.20 (s, 1H), 9.23 (s, 1H), 8.19 (d, 1H),
7.90 (dd, 1H), 7.53 (d, 1H), 7.41 (m, 4H), 7.33 (m, 1H), 7.17 (d,
1H), 6.86 (dd, 1H), 6.70 (dd, 1H), 6.41 (m, 1H), 6.21 (d, 1H), 3.84
(dd, 2H), 3.57 (m, 4H), 3.26 (m, 6H), 3.00 (m, 2H), 2.74 (s, 2H),
2.18 (s, 2H), 2.01 (s, 2H), 1.83 (m, 1H), 1.54 (m, 2H), 1.45 (t,
2H), 1.23 (m, 2H), 0.94 (s, 6H).
Example 305
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4,4-difluorocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H--
indol-5-yloxy)benzamide
This example was prepared by substituting
4,4-difluorocyclohexanamine, hydrochloric Acid for
(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in
EXAMPLE 187B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.16 (s, 2H), 8.59 (d, 1H), 8.25 (d, 1H), 7.84 (dd, 1H),
7.50 (d, 2H), 7.39-7.41 (m, 2H), 7.33 (d, 2H), 7.15-7.18 (m, 2H),
7.03 (d, 2H), 6.85 (dd, 1H), 6.65 (dd, 1H), 6.39 (s, 1H), 6.14 (d,
1H), 3.86 (d, 1H), 3.04 (s, 4H), 2.74 (s, 2H), 1.95-2.18 (m, 14H),
1.69-1.73 (m, 2H), 1.38 (d, 2H), 0.92 (s, 6H).
Example 306
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulf-
onyl)-2-(1H-indol-4-yloxy)benzamide
Example 306A
1,6-dioxaspiro[2.5]octane-2-carbonitrile
A mixture of dihydro-2H-pyran-4(3H)-one (10.0 g) and
2-chloroacetonitrile (7.55 g) in tert-butanol (10 mL) was treated
with 1.0 N potassium tert-butoxide (100 mL) drop-wise over 20
minutes. The reaction mixture was stirred at room temperature for
16 hours. It was diluted with water (10 mL) and 10% HCl (20 mL).
The reaction mixture was concentrated to one-third of its original
volume, and extracted with diethyl ether four times.
The combined organic layers were washed with brine, dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified
with flash column chromatography on silica gel eluting with 20-40%
ethyl acetate in hexanes to give the title compound.
Example 306B
2-(4-fluorotetrahydro-2H-pyran-4-yl)-2-hydroxyacetonitrile
EXAMPLE 306A (11.5 g) was dissolved in dichloromethane (40 mL) in a
polypropylene bottle. The bottle was cooled to 0.degree. C. To this
mixture was added 70% hydrogen fluoride-pyridine (10.31 mL) slowly.
The mixture was allowed to warm to room temperature over 3 hours,
and stirred for 24 hours. The reaction mixture was diluted with
ethyl acetate (200 mL) and poured into saturated aqueous
NaHCO.sub.3. Additional solid NaHCO.sub.3 was used to neutralize
the mixture carefully until bubbling ceased. The organic layer was
isolated, and the aqueous layer was extracted with additional ethyl
acetate three times (150 mL each). The combined organic layers were
washed with 1% HCl, brine, dried (MgSO.sub.4), filtered and
concentrated to give the desired compound which was used directly
in the next reaction.
Example 306C
(4-fluorotetrahydro-2H-pyran-4-yl)methanol
EXAMPLE 306B (11.78 g) in 2-propanol (150 mL) and water (37.5 mL)
was cooled to 0.degree. C. To this mixture was added sodium
borohydride (4.2 g). The mixture was stirred and allowed to warm to
room temperature over 3 hours. The reaction was quenched with
acetone, and stirred for another 1 hour. The clear liquid was
separated from solid by decanting. Additional ethyl acetate was
used to wash the solid, and was decanted. The combined organic
solution was concentrated. The residue was purified with flash
column chromatography on silica gel eluting with 20-40% ethyl
acetate in hexanes to give the title compound.
Example 306D
4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide
This example was prepared by substituting EXAMPLE 306C for
(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 279A.
Example 306E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulf-
onyl)-2-(1H-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 306D for EXAMPLE
1F and EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.24 (s, 1H), 8.28 (d,
1H), 7.98 (dd, 1H), 7.54 (d, 1H), 7.42 (d, 1H), 7.34 (d, 2H), 7.28
(t, 1H), 7.17 (d, 1H), 7.04 (d, 2H), 6.97 (t, 1H), 6.70 (dd, 1H),
6.41 (d, 1H), 6.26-6.28 (m, 2H), 4.38 (d, 2H), 3.76-3.80 (m, 2H),
3.57-3.62 (m, 2H), 3.06 (s, 4H), 2.80 (s, 2H), 2.24 (br s, 2H),
2.15-2.25 (m, 2H), 1.96 (s, 2H), 1.82-1.89 (m, 4H), 1.39 (t, 2H),
0.93 (s, 6H).
Example 307
4-(4-(4-{[4-(4-chlorophenyl)-1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl]met-
hyl}piperazin-1-yl)-2-(l
1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]ph-
enyl}sulfonyl)benzamide
Example 307A
4-(4-chlorophenyl)-2-fluoro-5-methylpyridine
A mixture of 2-fluoro-4-iodo-5-methylpyridine (1.9 g),
4-chlorophenylboronic acid (1.504 g),
tetrakis(triphenylphosphine)palladium(O) (0.463 g), and sodium
carbonate (2.55 g) in ethanol (20 mL), water (10 mL) and toluene
(10 mL) was heated under reflux for 6 hours. The reaction mixture
was partitioned between ethyl acetate and water. The organic layer
was separated, and the aqueous layers were extracted with
additional ethyl acetate three times. The combined organic layers
were washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified with flash column
chromatography on silica gel using 5% ethyl acetate in hexanes to
give the title compound.
Example 307B
5-(bromomethyl)-4-(4-chlorophenyl)-2-fluoropyridine
A mixture of EXAMPLE 307A (1.2 g), N-bromosuccinimide (1.06 g) and
AIBN (azobisisobutyronitrile) (0.178 g) in CCl.sub.4 (30 mL) was
heated under reflux for 6 hours. After cooling, the solid was
filtered off. The filtrate was concentrated and loaded onto a
silica gel column eluting with 3% ethyl acetate in hexanes to give
the title compound.
Example 307C
tert-butyl
4-((4-(4-chlorophenyl)-6-fluoropyridin-3-yl)methyl)piperazine-1-
-carboxylate
A mixture of EXAMPLE 307B (1.24 g), tert-butyl
piperazine-1-carboxylate (0.768 g), and potassium carbonate (0.570)
in N,N-dimethylformamide (20 mL) was stirred at room temperature
for 2 hours. The reaction mixture was partitioned between ethyl
acetate and water. The organic layer was separated, and the aqueous
layer was extracted with additional ethyl acetate three times. The
combined organic layers were washed with brine, dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified
with flash column chromatography on silica gel using 10% ethyl
acetate in hexanes to give the title compound.
Example 307D
tert-butyl
4-((4-(4-chlorophenyl)-6-oxo-1,6-dihydropyridin-3-yl)methyl)pip-
erazine-1-carboxylate
A mixture of EXAMPLE 307C (1.6 g) and 5% HCl (20 mL) in
tetrahydrofuran (20 mL) was heated at 80.degree. C. overnight. The
solvent was removed to dryness. This solid was re-dissolved and
added to tetrahydrofuran (50 mL). To this mixture were added
BOC.sub.2O (di-t-butyl-dicarbonate) (1.118 g), triethylamine (0.72
mL), and 4-dimethylamionpyridine (1.4 g).
The solvent was removed, and the residue was partitioned between
water and ethyl acetate.
The reaction mixture was stirred overnight. The organic layers were
dried (MgSO.sub.4), filtered, and concentrated. The residue was
purified by Prep HPLC eluting with 20-100% acetonitrile/water with
0.1% trifluoroacetic acid to give the title compound.
Example 307E
tert-butyl
4-((4-(4-chlorophenyl)-1-isopropyl-6-oxo-1,6-dihydropyridin-3-y-
l)methyl)piperazine-1-carboxylate
EXAMPLE 307D (0.404 g) in N,N-dimethylformamide (5 mL) was treated
with 60% sodium hydride (0.24 g) at room temperature. To this
mixture was added 2-iodopropane (0.204 g). The mixture was stirred
overnight. The reaction mixture was partitioned between ethyl
acetate and water. The organic layer was separated, and the aqueous
layers were extracted with additional ethyl acetate three times.
The combined organic layers were washed with brine, dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified
with flash column chromatography on silica gel using 10% ethyl
acetate in hexanes to give EXAMPLE 307E and EXAMPLE 307F.
Example 307F
tert-butyl
4-((4-(4-chlorophenyl)-6-isopropoxypyridin-3-yl)methyl)piperazi-
ne-1-carboxylate
This compound was isolated as a by-product during the preparation
of EXAMPLE 307E.
Example 307G
4-(4-chlorophenyl)-1-isopropyl-5-(piperazin-1-ylmethyl)pyridin-2(1H)-one
This example was prepared by substituting EXAMPLE 307E for EXAMPLE
1A in EXAMPLE 1B.
Example 307H
ethyl
2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-1-isopropyl-6-oxo-1,6-
-dihydropyridin-3-yl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 307G for EXAMPLE
20C and EXAMPLE 26A for EXAMPLE 20A in EXAMPLE 20D.
Example 307I
2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-1-isopropyl-6-oxo-1,6-dihyd-
ropyridin-3-yl)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 307H for EXAMPLE
1D in EXAMPLE 1E.
Example 307J
4-(4-{[4-(4-chlorophenyl)-1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl]methyl-
}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran--
4-ylmethyl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 3071 for EXAMPLE
26C in EXAMPLE 177. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.07 (s, 1H), 8.62 (t, 1H),
8.59 (d, 1H), 7.79 (dd, 1H), 7.59 (s, 1H), 7.52-7.53 (m, J 3H),
7.38-7.45 (m, 4H), 7.15 (d, 1H), 7.10 (d, 1H), 6.87 (dd, 1H), 6.68
(dd, 1H), 6.39 (s, 1H), 6.22 (s, 1H), 6.17 (d, 1H), 5.01-5.06 (m,
1H), 3.85 (dd, 2H), 3.24-3.31 (m, 6H), 3.09 (s, 2H), 3.00 (s, 4H),
2.26 (m, 4H), 2.09 (m, 2H), 1.60-1.63 (m, 2H), 1.30 (d, 6H).
Example 308
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]c-
arbonyl}phenyl)sulfonyl]benzamide
Example 308A
4-sulfamoyl-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide
4-Sulfamoylbenzoic acid (201 mg),
(tetrahydro-2H-pyran-4-yl)methanamine (144 mg),
1-hydroxybenzotriazole hydrate (230 mg), and
1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (288
mg) were combined in acetonitrile.
The mixture was stirred at room temperature overnight. The solids
were filtered off and reaction mixture was concentrated. The crude
material was purified by flash chromatography eluting with a
gradient of 2% methanol/dichloromethane to 10%
methanol/dichloromethane.
Example 308B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]c-
arbonyl}phenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 308A for EXAMPLE
1F and EXAMPLE 26C for EXAMPLE 1E in EXAMPLE 1G. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.19 (s, 1H), 8.57 (t,
1H), 7.94 (m, 4H), 7.48 (d, 1H), 7.43 (d, 1H), 7.40 (t, 1H), 7.33
(d, 2H), 7.21 (d, 1H), 7.03 (d, 2H), 6.88 (dd, 1H), 6.63 (dd, 1H),
6.42 (t, 1H), 6.13 (d, 1H), 3.84 (dd, 2H), 3.26 (m, 2H), 3.16 (t,
2H), 3.03 (br s, 4H), 2.74 (br s, 2H), 2.15 (m, 6H), 1.95 (s, 2H),
1.79 (m, 1H), 1.59 (d, 2H), 1.38 (t, 2H), 1.19 (m, 2H), 0.92 (s,
6H).
Example 309
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluorometh-
yl)sulfonyl]phenyl}sulfonyl)benzamide
Example 309A
4-(2-methoxyethylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide
This example was prepared by substituting EXAMPLE 159C for
4-fluoro-3-nitrobenzenesulfonamide and 2-methoxyethylamine for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 309B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluorometh-
yl)sulfonyl]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
26C and EXAMPLE 309A for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.26 (s, 1H), 8.13
(d, 1H), 7.79 (dd, 1H), 7.51 (d, 1H), 7.34 (d, 2H), 7.29 (t, 1H),
7.24 (m, 1H), 7.19 (d, 1H), 7.04 (d, 2H), 6.99 (m, 3H), 6.70 (dd,
1H), 6.44 (d, 1H), 6.27 (m, 2H), 3.52 (m, 4H), 3.28 (s, 3H), 3.05
(m, 4H), 2.75 (s, 2H), 2.17 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H),
0.92 (s, 6H).
Example 310
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-indol-5-yloxy)benzamide
Example 310A
4-(aminomethyl)cyclohexanol
The title compound was prepared as described in EXAMPLE 311A by
replacing (4-methoxyphenyl)methanamine with
(4-hydroxyphenyl)methanamine.
Example 310B
2-(1H-indol-5-yloxy)-N-(4-chloro-3-nitrophenylsulfonyl)-4-(4-((2-(4-chloro-
phenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide
The title compound was prepared as described in EXAMPLE 1G by
replacing EXAMPLE 1E and EXAMPLE 1F with EXAMPLE 26C and
4-chloro-3-nitrobenzenesulfonamide.
Example 310C
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(1H-indol-5-yloxy)benzamide
A mixture of EXAMPLE 310B (100 mg), triethylamine (0.2 ml) and
EXAMPLE 310A (35 mg) in dioxane (5 ml) was heated at 100.degree. C.
for 20 hours and concentrated. The residue was purified by RP-HPLC
(10-70% acetonitrile in 0.1% trifluoroacetic acid water/70 minutes)
to provide the title compound as a trifluroacetic acid salt.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.40 (s,
1H), 11.18 (s, 1H), 9.20 (s, 1H), 8.60 (t, 1H), 8.58 (d, 1H), 7.77
(dd, 1H), 7.54 (d, 1H), 7.42 (s, 1H), 7.37-7.41 (m, 3H), 7.14 (d,
1H), 7.04-7.09 (m, 3H), 6.86 (dd, 1H), 6.69 (dd, 1H), 6.39 (s, 1H),
6.21 (s, 1H), 3.50-3.68 (m, 3H), 3.20-3.27 (m, 3H), 2.93-3.07 (m,
2H), 2.66-2.82 (m, 2H), 2.13-2.22 (m, 2H), 2.01 (s, 2H), 1.83 (d,
2H), 1.67-1.77 (m, 3H), 1.50-1.60 (m, 1H), 1.44 (s, 2H), 0.96-1.17
(m, 4H), 0.94 (s, 6H).
Example 311
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino-
}-3-nitrophenyl)sulfonyl]benzamide
Example 311A
(4-methoxycyclohexyl)methanamine
(4-Methoxyphenyl)methanamine (1 g) in ethanol (10 ml) was treated
with 5% dry Rh--Al.sub.2O.sub.3 (0.5 g) under H.sub.2 (500 psi) at
60.degree. C. for 6 hours and then at 125.degree. C. for 26 hours.
The insoluble material was filtered off and the filtrate was
concentrated to provide the title compound.
Example 311B
4-(((Trans-4-methoxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide
4-fluoro-3-nitrobenzenesulfonamide (15 g) and EXAMPLE 311A (11.71
g) in tetrahydrofuran (200 ml) was treated with triethylamine (28.5
ml) overnight. The reaction was concentrated and the residue was
loaded onto a C18 column, and eluted with 40-55% acetonitrile in
water to provide the title compound.
Example 311C
4-(((Cis-4-methoxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide
This compound was made from the same procedure that also produced
EXAMPLE 311B.
Example 311D
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino-
}-3-nitrophenyl)sulfonyl]benzamide
The title compound was prepared as described in EXAMPLE 175F by
replacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE
311B, respectively. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.17 (s, 2H), 8.55-8.62 (m,
2H), 7.78 (dd, 1H), 7.51 (d, 1H), 7.37-7.43 (m, 2H), 7.33 (d, 2H),
7.15 (d, 1H), 7.01-7.08 (m, 3H), 6.86 (dd, 1H), 6.65 (dd, 1H), 6.39
(s, 1H), 6.14 (d, 1H), 3.25 (t, 2H), 3.22 (s, 3H), 3.00-3.10 (m,
5H), 2.72 (s, 2H), 2.15 (d, 6H), 2.00 (d, 2H), 1.94 (s, 2H), 1.78
(d, 2H), 1.53-1.65 (m, 1H), 1.38 (t, 2H), 0.96-1.12 (m, 4H), 0.92
(s, 6H).
Example 312
Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfony-
l]-2-(1H-indol-5-yloxy)benzamide
The title compound (trifluroacetic acid salt) was obtained during
the purification of EXAMPLE 310C. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.39 (s, 1H), 11.18 (s, 1H),
9.17 (s, 1H), 8.61 (t, 1H), 8.58 (d, 1H), 7.78 (dd, 1H), 7.54 (d,
1H), 7.34-7.43 (m, 5H), 7.14 (d, 1H), 7.07 (t, 3H), 6.85 (dd, 1H),
6.69 (d, 1H), 6.39 (s, 1H), 6.21 (s, 1H), 3.77 (s, 1H), 3.58 (s,
2H), 3.24-3.29 (m, 2H), 2.91-3.07 (m, 2H), 2.60-2.81 (m, 2H), 2.17
(s, 2H), 2.00 (s, 2H), 1.57-1.72 (m, 4H), 1.43 (t, 7H), 0.94 (s,
6H).
Example 313
Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}--
3-nitrophenyl)sulfonyl]benzamide
The title compound was prepared as described in EXAMPLE 175F by
replacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE
311C, respectively. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.17 (s, 2H), 8.60 (t, 1H),
8.58 (d, 1H), 7.78 (dd, 1H), 7.51 (d, 1H), 7.37-7.44 (m, 2H), 7.33
(d, 2H), 7.16 (d, 1H), 7.07 (d, 1H), 7.03 (d, 2H), 6.86 (dd, 1H),
6.65 (dd, 1H), 6.39 (s, 1H), 6.14 (d, 1H), 3.36-3.39 (m, 1H), 3.26
(t, 2H), 3.20 (s, 3H), 3.03 (s, 4H), 2.72 (s, 2H), 2.15 (d, 6H),
1.94 (s, 2H), 1.81 (dd, 2H), 1.63-1.73 (m, 1H), 1.48 (dd, 2H),
1.23-1.41 (m, 6H), 0.92 (s, 6H).
Example 314
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethoxy-
)phenyl]sulfonyl}benzamide
Example 314A
3-nitro-4-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)benzenesulfonamide
This example was prepared by substituting
2-(tetrahydro-2H-pyran-4-yl)ethanol for
(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 279A.
Example 314B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethoxy-
)phenyl]sulfonyl}benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
26C and EXAMPLE 314A for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.25 (s, 1H), 8.25
(d, 1H), 7.95 (dd, 1H), 7.54 (d, 1H), 7.39 (d, 1H), 7.34 (d, 2H),
7.29 (m, 1H), 7.17 (m, 1H), 7.04 (d, 2H), 6.97 (m, 1H), 6.70 (dd,
1H), 6.41 (d, 1H), 6.28 (m, 2H), 4.26 (t, 2H), 3.83 (m, 2H), 3.27
(m, 2H), 3.07 (m, 4H), 2.80 (m, 2H), 2.15 (m, 6H), 1.96 (s, 2H),
1.70 (m, 3H), 1.60 (m, 2H), 1.39 (t, 2H), 1.22 (m, 2H), 0.93 (s,
6H).
Example 315
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluorometh-
yl)sulfonyl]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 309A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.17 (s, 1H), 8.18 (d, 1H), 7.92 (dd, 1H), 7.49 (d, 1H),
7.40 (m, 2H), 7.33 (d, 2H), 7.26 (m, 1H), 7.17 (d, 1H), 7.04 (m,
3H), 6.86 (dd, 1H), 6.65 (dd, 1H), 6.40 (m, 1H), 6.14 (d, 1H), 3.51
(m, 4H), 3.28 (s, 3H), 3.03 (s, 4H), 2.74 (m, 2H), 2.16 (m, 6H),
1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 316
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({4-[3-(methylsulfonyl)propoxy]-3-nitrophenyl-
}sulfonyl)benzamide
Example 316A
4-(3-(methylthio)propoxy)-3-nitrobenzenesulfonamide
This example was prepared by substituting 3-(methylthio)propan-1-ol
for (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 279A.
Example 316B
4-(3-(methylsulfonyl)propoxy)-3-nitrobenzenesulfonamide
This example was prepared by substituting EXAMPLE 316A for EXAMPLE
294A in EXAMPLE 294B.
Example 316C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({4-[3-(methylsulfonyl)propoxy]-3-nitrophenyl-
}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
26C and EXAMPLE 316B for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.24 (s, 1H), 8.28
(d, 1H), 7.96 (dd, 1H), 7.54 (d, 1H), 7.35 (m, 3H), 7.29 (t, 1H),
7.17 (d, 1H), 7.04 (d, 2H), 6.96 (m, 1H), 6.71 (dd, 1H), 6.39 (d,
1H), 6.29 (m, 2H), 4.34 (t, 2H), 3.27 (m, 4H), 3.07 (m, 4H), 3.03
(s, 3H), 2.81 (s, 2H), 2.21 (m, 6H), 1.96 (s, 2H), 1.39 (t, 2H),
0.93 (s, 6H).
Example 317
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}su-
lfonyl)benzamide
Example 317A
4-(3-methoxypropylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting 3-methoxypropan-1-amine
for (tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 317B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}su-
lfonyl)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 317A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (500
MHz, pyridine-d.sub.5) .delta. 12.24 (s, 1H), 9.30 (d, 1H), 8.88
(t, 1H), 8.28 (dd, 1H), 8.19 (d, 1H), 7.51-7.56 (m, 2H), 7.41-7.46
(m, 3H), 7.04-7.12 (m, 3H), 6.78 (d, 1H), 6.73 (dd, 1H), 6.60 (s,
1H), 6.55 (d, 1H), 3.40 (t, 2H), 3.29-3.36 (m, 2H), 3.27 (s, 3H),
3.01-3.08 (m, 4H), 2.76 (s, 2H), 2.25 (t, 2H), 2.06-2.15 (m, 4H),
1.97 (s, 2H), 1.78-1.86 (m, 2H), 1.38 (t, 2H), 0.93 (s, 6H).
Example 318
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}su-
lfonyl)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 317A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (500
MHz, pyridine-d.sub.5) .delta. 12.39 (s, 1H), 9.21 (d, 1H), 8.86
(t, 1H), 8.15-8.24 (m, 2H), 7.42-7.50 (m, 3H), 7.38 (d, 1H),
7.04-7.13 (m, 3H), 6.73-6.81 (m, 4H), 6.67 (d, 1H), 3.39 (t, 2H),
3.32 (q, 2H), 3.27 (s, 3H), 2.96-3.07 (m, 4H), 2.76 (s, 2H), 2.25
(t, 2H), 2.07-2.16 (m, 4H), 1.97 (s, 2H), 1.77-1.87 (m, 2H), 1.39
(t, 2H), 0.94 (s, 6H).
Example 319
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yl-
oxy)benzamide
Example 319A
4-(2-cyanoethylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting 3-aminopropanenitrile for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 319B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yl-
oxy)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 319A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (500
MHz, pyridine-d.sub.5) .delta. 9.26 (d, 1H), 9.06 (t, 1H), 8.34
(dd, 1H), 8.18 (d, 1H), 7.51-7.57 (m, 2H), 7.39-7.47 (m, 3H),
7.04-7.11 (m, 3H), 7.00 (d, 1H), 6.74 (dd, 1H), 6.60 (s, 1H), 6.54
(d, 1H), 3.83 (q, J=6.7 Hz, 2H), 3.01-3.08 (m, 4H), 2.98 (t, 2H),
2.76 (s, 2H), 2.25 (t, 2H), 2.07-2.15 (m, 4H), 1.97 (s, 2H), 1.38
(t, 2H), 0.93 (s, 6H).
Example 320
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-yl-
oxy)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and EXAMPLE 319A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (500
MHz, pyridine-d.sub.5) .delta. 12.41 (s, 1H), 9.16 (d, 1H), 9.05
(t, 1H), 8.31 (dd, 1H), 8.17 (d, 1H), 7.39 (d, 1H), 7.05-7.13 (m,
3H), 6.99 (d, 1H), 6.78 (dd, 1H), 6.72-6.76 (m, 2H), 6.66 (d, 1H),
3.83 (q, 2H), 3.01-3.07 (m, 4H), 2.98 (t, 2H), 2.76 (s, 2H), 2.25
(t, 2H), 2.08-2.16 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s,
6H).
Example 321
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[(3R)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulf-
onyl}-2-(1H-indol-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 310C by
replacing EXAMPLE 310A with 5-aminomethyl-admantan-2-ol. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.17 (s, 2H),
8.57 (d, 1H), 8.51 (t, 1H), 7.76 (dd, 1H), 7.50 (d, 1H), 7.38-7.42
(m, 2H), 7.33 (d, 2H), 7.11-7.16 (m, 2H), 7.03 (d, 2H), 6.86 (dd,
1H), 6.65 (dd, 1H), 6.39 (s, 1H), 6.14 (d, 1H), 4.61 (d, 1H), 3.63
(d, 1H), 3.13 (d, 2H), 3.03 (s, 4H), 2.73 (s, 2H), 2.11-2.21 (m,
6H), 2.04 (d, 2H), 1.95 (s, 2H), 1.78-1.86 (m, 3H), 1.49-1.60 (m,
6H), 1.38 (t, 2H), 1.29 (d, 2H), 0.92 (s, 6H).
Example 322
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({[Cis-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfo-
nyl}-2-(1H-indol-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 310C by
replacing EXAMPLE 310A with 5-aminomethyl-admantan-2-ol. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.16 (s, 2H),
8.57 (d, 1H), 8.52 (t, 1H), 7.71-7.80 (m, 1H), 7.51 (d, 1H),
7.37-7.42 (m, 2H), 7.33 (d, 2H), 7.09-7.17 (m, 2H), 7.03 (d, 2H),
6.85 (dd, 1H), 6.65 (dd, 1H), 6.39 (s, 1H), 6.14 (d, 1H), 4.61 (d,
1H), 3.61 (d, 1H), 3.08 (d, 2H), 3.03 (s, 4H), 2.72 (s, 2H),
2.09-2.21 (m, 6H), 1.82-1.96 (m, 7H), 1.55-1.69 (m, 4H), 1.49 (s,
2H), 1.38 (t, 2H), 1.19-1.27 (m, 3H), 0.92 (s, 6H).
Example 323
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phe-
nyl}sulfonyl)benzamide
Example 323A
3-nitro-4-(3,3,3-trifluoropropylamino)benzenesulfonamide
This example was prepared by substituting
3,3,3-trifluoropropan-1-amine for
(tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 1F.
Example 323B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phe-
nyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 323A for EXAMPLE
1F and EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.34 (s, 1H), 11.19 (s,
1H), 8.53 (m, 1H), 8.47 (s, 1H), 7.74 (dd, 1H), 7.54 (d, 1H), 7.34
(d, 2H), 7.25 (m, 1H), 7.13 (d, 1H), 6.99 (m, 4H), 6.67 (d, 1H),
6.36 (d, 1H), 6.24 (m, 2H), 3.65 (q, 2H), 3.01 (m, 4H), 2.68 (m,
4H), 2.16 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.93 (s, 6H).
Example 324
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phe-
nyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 323A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.06 (s, 1H), 8.44 (m, 2H), 7.75 (dd, 1H), 7.54 (d, 1H),
7.33 (m, 4H), 7.02 (m, 3H), 6.90 (d, 1H), 6.76 (dd, 1H), 6.58 (dd,
1H), 6.33 (m, 1H), 6.15 (d, 1H), 3.63 (q, 2H), 2.97 (m, 4H), 2.68
(m, 4H), 2.16 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s,
6H).
Example 325
N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl-
)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-(1H-indol-4-yloxy)benzamide
Example 325A
5-bromo-6-((tetrahydro-2H-pyran-4-yl)methylamino)pyridine-3-sulfonamide
The mixture of EXAMPLE 329A (93 mg),
(tetrahydro-2H-pyran-4-yl)methanamine (40 mg) and triethylamine
(0.144 mL) in anhydrous dixoane (4 mL) was heated at 110.degree. C.
overnight. The organic solvent was removed under vacuum. The
residue was suspended in dichloromethane. The solid was filtered
and dried to afford the title compound.
Example 325B
N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl-
)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-(1H-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
26C and EXAMPLE 325A for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.28 (s, 1H), 11.10
(s, 1H), 8.38 (d, 1H), 7.93 (d, 1H), 7.57 (d, 1H), 7.32 (m, 4H),
7.22 (d, 1H), 7.02 (m, 3H), 6.71 (dd, 1H), 6.51 (d, 1H), 6.27 (m,
2H), 3.82 (dd, 2H), 3.31 (m, 2H), 3.23 (m, 2H), 3.05 (m, 4H), 2.74
(s, 2H), 2.16 (m, 6H), 1.95 (s, 2H), 1.88 (m, 1H), 1.55 (m, 2H),
1.37 (m, 2H), 1.18 (m, 2H), 0.92 (s, 6H).
Example 326
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}-3-nitrophenyl-
)sulfonyl]-2-(1H-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 337A for
4-chloro-3-nitrobenzene sulfonamide and
(1,1-dioxidotetrahydrothien-3-yl)methylamine hydrochloride for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.25 (s, 1H),
8.71 (m, 1H), 8.51 (d, 1H), 7.72 (dd, 1H), 7.53 (d, 1H), 7.34 (d,
2H), 7.29 (m, 1H), 7.18 (d, 1H), 7.12 (d, 1H), 7.04 (d, 2H), 6.98
(m, 1H), 6.70 (dd, 1H), 6.44 (d, 1H), 6.26 (dd, 2H), 3.55 (t, 2H),
3.27 (m, 2H), 3.04 (m, 5H), 2.91 (m, 1H), 2.74 (s, 3H), 2.28 (m,
1H), 2.16 (m, 6H), 1.95 (s, 2H), 1.85 (m, 1H), 1.38 (t, 2H), 0.92
(s, 6H).
Example 327
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulf-
onyl)-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 306D for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.16 (s, 2H), 8.41 (d, 1H), 8.10 (dd, 1H), 7.51 (d, 1H),
7.39-7.46 (m, 3H), 7.34 (d, 2H), 7.16 (s, 1H), 7.04 (d2H), 6.85
(dd, 1H), 6.64 (dd, 1H), 6.40 (d, 1H), 6.15 (d, 1H), 4.38 (d, 2H),
3.76-3.80 (m, 2H), 3.56-3.61 (m, 2H), 3.05 (s, 4H), 2.78 (s, 2H),
2.12-2.23 (m, 6H), 1.95 (s, 2H), 1.80-1.89 (m, 4H), 1.38 (t, 2H),
0.92 (s, 6H).
Example 328
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-(methylamino)-3-[(trifluoromethyl)sulfony-
l]phenyl}sulfonyl)benzamide
Example 328A
4-(methylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide
This example was prepared by substituting EXAMPLE 159C for
4-fluoro-3-nitrobenzenesulfonamide and methylamine for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 328B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-(methylamino)-3-[(trifluoromethyl)sulfony-
l]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 328A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.17 (s, 1H), 8.17 (d, 1H), 7.91 (dd, 1H), 7.49 (d, 1H),
7.40 (m, 3H), 7.33 (d, 2H), 7.16 (m, 1H), 7.04 (d, 2H), 6.87 (m,
2H), 6.65 (dd, 1H), 6.40 (m, 1H), 6.14 (d, 1H), 3.03 (m, 4H), 2.91
(d, 3H), 2.73 (s, 2H), 2.15 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H),
0.92 (s, 6H).
Example 329
N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-
-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl-
)-2-(1H-indol-5-yloxy)benzamide
Example 329A
5-bromo-6-chloropyridine-3-sulfonamide
5-Bromo-6-chloropyridine-3-sulfonyl chloride (8.2 g) in methanol
(20 mL) was cooled to 0.degree. C. To this mixture was added 7N
NH.sub.3 in methanol (80 mL). The reaction mixture was stirred
overnight. The solvent was removed at low temperature, and the
residue was partitioned between ethyl acetate and water. The
aqueous layer was extracted with ethyl acetate three times. The
combined organic layers were washed with brine, dried (MgSO.sub.4),
filtered, and concentrated. The solid was purified by flash column
chromatography on silica gel using 10-50% ethyl acetate in hexanes
to give the title compound.
Example 329B
5-bromo-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
(Tetrahydro-2H-pyran-4-yl)methanol (0.65 g) in tetrahydrofuran (20
mL) was treated with 60% sodium hydride (0.895 g). The reaction
mixture was stirred for 10 minutes. To this mixture was added
EXAMPLE 329A (1.519 g). The reaction mixture was stirred overnight.
It was poured into water, neutralized with 10% aqueous HCl, and
extracted with ethyl acetate three times. The combined organic
layers were washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified with flash column
chromatography on silica gel eluting with 20%-60% ethyl acetate in
hexanes to give the title compound.
Example 329C
N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-
-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl-
)-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 329B for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.15 (s, 1H), 8.60 s, 1H), 8.38 (d, 1H), 7.54 (d, 1H),
7.38-7.42 (m, 2H), 7.34 (d, 2H), 7.17 (s, 1H), 7.04 (d, 2H), 6.85
(dd, 1H), 6.64 (dd, 1H), 6.39 (s, 1H), 6.14 (d, 1H), 4.25 (d, 2H),
3.87 (dd, 2H), 3.05 (s, 4H), 2.80 (s, 2H), 2.25 (s, 4H), 2.12-2.14
(m, 4H), 1.95 (s, 2H), 1.63-1.66 (m, 2H), 1.37-1.40 (m, 2H), 0.92
(s, 6H).
Example 330
4-(4-{[4-(4-chlorophenyl)-6-isopropoxypyridin-3-yl]methyl}piperazin-1-yl)--
2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-
phenyl}sulfonyl)benzamide
Example 330A
1-((4-(4-chlorophenyl)-6-isopropoxypyridin-3-yl)methyl)piperazine
This example was prepared by substituting EXAMPLE 307F for EXAMPLE
1A in EXAMPLE 1B.
Example 330B
ethyl
2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6-isopropoxypyridin-3-
-yl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 330A for EXAMPLE
20C and EXAMPLE 26A for EXAMPLE 20A in EXAMPLE 20D.
Example 330C
2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6-isopropoxypyridin-3-yl)me-
thyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 330B for EXAMPLE
1D in EXAMPLE 1E.
Example 330D
4-(4-{[4-(4-chlorophenyl)-6-isopropoxypyridin-3-yl]methyl}piperazin-1-yl)--
2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-
phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 330C for EXAMPLE
26C in EXAMPLE 177. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.21, (s, 1H), 11.17 (s, 1H),
8.63 (t, 1H), 8.59 (d, 1H), 8.08 (s, 1H), 7.79 (dd1H), 7.54-7.56
(m, 3H), 7.47 (d, 2H), 7.38-7.42 (m, 2H), 7.15 (d, 1H), 7.10 (d,
1H), 6.87 (dd, 1H), 6.68 (dd, 1H), 6.59 (s, 1H), 6.39 (s, 1H), 6.17
(d, 1H), 5.23-5.28 (m, 1H), 3.85 (dd, 2H), 3.24-3.31 (m, 4H), 3.02
(s, 4H), 2.29 (s, 4H), 1.86-1.91 (m, 1H), 1.61-1.63 (m, 2H), 1.28
(d, 6H).
Example 331
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(1,3--
thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamide
Example 331A
6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(thiazol-2-yl)pyridine-3-sulfonami-
de
A mixture of EXAMPLE 329B (0.070 g), 2-(tributylstannyl)thiazole
(0.090 g), and tetrakis(triphenylphosphine)palladium(O) (0.069 g)
in dioxane (2 mL) was heated at 90.degree. C. for 4 hours. After
cooling, the mixture was loaded onto a silica gel column and
eluting with 1:3 ethyl acetate:hexanes to give the title
compound.
Example 331B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(1,3--
thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamide
This example was prepared by substituting EXAMPLE 331A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.14 (s, 1H), 9.09 (s, 1H), 8.73 (s, 1H), 8.06 (d, 1H),
7.98 (d, 1H), 7.50 (d, 1H), 7.37-7.38 (m, 2H), 7.33 (d, 2H), 7.17
(d, 1H), 7.03 (d, 2H), 6.84 (dd, 1H), 6.62 (dd, 1H), 6.37 (s, 1H),
6.11 (d, 1H), 4.46 (d, 2H), 3.91 (dd, 2H), 3.36-3.39 (m, 4H), 3.02
(s, 4H), 2.76 (s, 2H), 2.12-2.20 (s, 8H), 1.94 (s, 2H), 1.45-1.47
(m, 2H), 1.37 (t, 2H), 0.91 (s, 6H).
Example 332
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(2-methoxyethyl)amino]carbonyl}phenyl)s-
ulfonyl]benzamide
Example 332A
N-(2-methoxyethyl)-4-sulfamoylbenzamide
This example was prepared by substituting 2-methoxyethanamine for
(tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 308A.
Example 332B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(2-methoxyethyl)amino]carbonyl}phenyl)s-
ulfonyl]benzamide
This example was prepared by substituting EXAMPLE 332A for EXAMPLE
1F and EXAMPLE 26C for EXAMPLE 1E in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) t 11.28 (br s, 1H), 11.17 (s, 1H),
8.71 (m, 1H), 7.94 (m, 4H), 7.48 (d, 1H), 7.41 (m, 2H), 7.33 (d,
2H), 7.21 (d, 1H), 7.03 (d, 2H), 6.88 (dd, 1H), 6.63 (dd, 1H), 6.42
(t, 1H), 6.13 (d, 1H), 3.45 (m, 4H), 3.27 (s, 3H), 3.03 (m, 4H),
2.73 (br s, 2H), 2.16 (m, 6H), 1.95 (br s, 2H), 1.38 (m, 2H), 0.92
(s, 6H).
Example 333
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl-
}-2-(1H-indol-5-yloxy)benzamide
Example 333A
5-cyano-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
A mixture of EXAMPLE 329B (0.702 g), dicyanozinc (0.129 g), and
tetrakis(triphenylphosphine)palladium(O) (0.231 g) in
N,N-dimethylformamide (2 mL) was degassed via vacuum/nitrogen cycle
three times. The reaction mixture was heated at 120.degree. C. for
3 hours. After cooling, it was poured into water and extracted with
ethyl acetate three times. The combined organic layers were washed
with brine, dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified with flash column chromatography on silica gel
eluting with 20%-60% ethyl acetate in hexanes to give the title
compound.
Example 333B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl-
}-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 333A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.17 (s, 1H), 8.84 (d, 1H), 8.64 (d, 1H), 7.57 (d, 1H),
7.38-7.41 (m, 4H), 7.12 (d, 1H), 7.08 (d, 2H), 6.87 (dd, 1H), 6.71
(dd, 1H), 6.38 (s, 1H), 6.23 (d, 1H), 4.31 (d, 2H), 3.88 (dd, 2H),
3.54 (br s, 2H), 3.02 (br s, 4H), 2.76 (br s, 2H), 2.18 (s, 4H),
2.01 (s, 2H), 1.63-1.66 (m, 2H), 1.49 (t, 2H), 0.94 (s, 6H).
Example 334
N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4--
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H--
indol-5-yloxy)benzamide
This example was prepared by substituting 1-acetylpiperidin-4-amine
for 1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 310B for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.16 (br s, 1H), 8.58
(d, 1H), 8.25 (d, 1H), 7.81 (dd, 1H), 7.51 (d, 1H), 7.43-7.37 (m,
2H), 7.34 (d, 2H), 7.19 (d, 1H), 7.15 (d, 1H), 7.04 (d, 2H), 6.85
(dd, 1H), 6.65 (dd, 1H), 6.39 (t, 1H), 6.15 (d, 1H), 4.32-4.23 (m,
1H), 3.96-3.77 (m, 2H), 3.21 (m, 2H), 3.03 (m, 4H), 2.80 (m, 2H),
2.73 (br s, 2H), 2.16 (m, 6H), 2.02 (s, 3H), 1.95 (br s, 2H),
1.65-1.44 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 335
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-
-3-nitrophenyl)sulfonyl]benzamide
This example was prepared by substituting
1-(methylsulfonyl)piperidin-4-amine for
1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.15 (br s, 1H), 8.59
(d, 1H), 8.25 (d, 1H), 7.82 (dd, 1H), 7.51 (d, 1H), 7.43-7.38 (m,
2H), 7.34 (d, 2H), 7.14 (m, 2H), 7.04 (d, 2H), 6.85 (dd, 1H), 6.65
(dd, 1H), 6.39 (t, 1H), 6.15 (d, 1H), 3.80 (m, 1H), 3.57 (m, 2H),
3.04 (m, 4H), 2.95 (m, 2H), 2.92 (br s, 3H), 2.73 (m, 2H), 2.15 (m,
6H), 2.06-1.98 (m, 2H), 1.95 (br s, 2H), 1.70 (m, 2H), 1.38 (t,
2H), 0.92 (s, 6H).
Example 336
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-((4-{[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H--
indol-5-yloxy)benzamide
Example 336A
4-((1,4-dioxan-2-yl)methylamino)-3-nitrobenzenesulfonamide
The title compound was prepared as described in EXAMPLE 1F by
replacing (tetrahydro-2H-pyran-4-yl)methanamine with
(1,4-dioxan-2-yl)methanamine.
Example 336B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-((4-{[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H--
indol-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 175F by
replacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE
336A, respectively. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.16 (s, 2H), 8.54-8.63 (m,
2H), 7.82 (dd, 1H), 7.50 (d, 1H), 7.38-7.42 (m, 2H), 7.33 (d, 2H),
7.16 (d, 1H), 7.10 (d, 1H), 7.03 (d, 2H), 6.86 (dd, 1H), 6.65 (dd,
1H), 6.39 (s, 1H), 6.14 (d, 1H), 3.76-3.82 (m, 3H), 3.57-3.68 (m,
2H), 3.45-3.52 (m, 2H), 3.36-3.42 (m, 1H), 3.03 (s, 4H), 2.73 (d,
2H), 2.10-2.22 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s,
6H).
Example 337
N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4--
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H--
indol-4-yloxy)benzamide
Example 337A
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
1E and 4-chloro-3-nitrobenzenesulfonamide for EXAMPLE 1F in EXAMPLE
1G.
Example 337B
N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4--
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H--
indol-4-yloxy)benzamide
This example was prepared by substituting 1-acetylpiperidin-4-amine
for 1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 337A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.24 (br s, 1H), 8.50
(d, 1H), 8.24 (d, 1H), 7.73 (dd, 1H), 7.52 (d, 1H), 7.34 (d, 2H),
7.27 (t, 1H), 7.19-7.13 (m, 2H), 7.04 (t, 2H), 6.97 (t, 1H), 6.70
(dd, 1H), 6.42 (d, 1H), 6.27 (dd, 1H), 6.24 (t, 1H), 4.29 (m, 1H),
3.97-3.78 (m, 2H), 3.22 (m, 2H), 3.05 (m, 4H), 2.81 (m, 2H), 2.72
(br s, 2H), 2.15 (m, 6H), 2.03 (s, 3H), 1.95 (br s, 2H), 1.66-1.44
(m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 338
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-
-3-nitrophenyl)sulfonyl]benzamide
This example was prepared by substituting
1-(methylsulfonyl)piperidin-4-amine for
1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 337A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.24 (br s, 1H), 8.50
(d, 1H), 8.25 (d, 1H), 7.74 (dd, 1H), 7.52 (d, 1H), 7.34 (d, 2H),
7.27 (t, 1H), 7.17 (d, 1H), 7.12 (d, 1H), 7.04 (d, 2H), 6.97 (t,
1H), 6.70 (dd, 1H), 6.42 (d, 1H), 6.27 (d, 1H), 6.24 (t, 1H), 3.81
(m, 1H), 3.58 (m, 2H), 3.05 (m, 4H), 2.96 (m, 2H), 2.92 (s, 3H),
2.74 (m, 2H), 2.16 (m, 6H), 2.06-1.98 (m, 2H), 1.95 (br s, 2H),
1.70 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 339
4-(4-{[4'-chloro-5-(trifluoromethyl)-1,1'-biphenyl-2-yl]methyl}piperazin-1-
-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)a-
mino]phenyl}sulfonyl)benzamide
Example 339A
methyl
2-(1H-indol-5-yloxy)-4-(4-(2-bromo-4-(trifluoromethyl)benzyl)pipera-
zin-1-yl)benzoate
This example was prepared by substituting
4-trifluoromethyl-2-bromobenzaldehyde for EXAMPLE 27C and EXAMPLE
150A for tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
Example 339B
methyl
2-(1H-indol-5-yloxy)-4-(4-((4'-chloro-5-(trifluoromethyl)biphenyl-2-
-yl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 339A for
2-fluoro-4-iodo-5-methylpyridine in EXAMPLE 307A.
Example 339C
2-(1H-indol-5-yloxy)-4-(4-((4'-chloro-5-(trifluoromethyl)biphenyl-2-yl)met-
hyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 339B for EXAMPLE
1D in EXAMPLE 1E.
Example 339D
4-(4-{[4'-chloro-5-(trifluoromethyl)-1,1'-biphenyl-2-yl]methyl}piperazin-1-
-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)a-
mino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 339C for EXAMPLE
26C in EXAMPLE 177. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.24, (s, 1H), 11.17 (s, 1H),
8.63 (t, 1H), 7.79 (dd, 1H), 7.72 (m, 2H), 7.38-7.53 (m, 8H), 7.15
(d, 1H), 7.10 (d, 1H), 6.87 (dd, 1H), 6.67 (dd, 1H), 6.39 (s, 1H),
6.16 (d, 1H), 3.85 (dd, 2H), 3.41 (s, 2H), 3.24-3.31 (m, 6H), 3.04
(s, 4H), 2.29 (s, 4H), 1.60-1.63 (m, 2H), 1.24-1.28 (m, 2H).
Example 340
4-(4-{[4'-chloro-5-(trifluoromethyl)-1,1'-biphenyl-2-yl]methyl}piperazin-1-
-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)p-
henyl]sulfonyl}benzamide
This example was prepared by substituting EXAMPLE 339C for EXAMPLE
26C and EXAMPLE 279A for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.40, (s, 1H), 11.17
(s, 1H), 8.41 (d, 1H), 8.07 (dd, 1H), 7.70-7.74 (m, 2H), 7.38-7.53
(m, 8H), 7.16 (d, 1H), 6.87 (dd, 1H), 6.67 (dd, 1H), 6.40 (s, 1H),
6.17 (d, 1H), 4.09 (d, 2H), 3.88 (dd, 2H), 3.42 (s, 2H), 3.05 (s,
4H), 2.30 (s, 4H), 2.00-2.05 (m, 1H), 1.63-1.66 (m, 2H), 1.31-1.37
(m, 2H).
Example 341
4-{4-[(5-tert-butyl-4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2--
(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]ph-
enyl}sulfonyl)benzamide
Example 341A
methyl
2-(1H-indol-5-yloxy)-4-(4-(2-bromo-4-tert-butylbenzyl)piperazin-1-y-
l)benzoate
This example was prepared by substituting
4-tert-butyl-2-bromobenzaldehyde for EXAMPLE 27C and EXAMPLE 150A
for tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
Example 341B
methyl
2-(1H-indol-5-yloxy)-4-(4-((5-tert-butyl-4'-chlorobiphenyl-2-yl)met-
hyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 341A for
2-fluoro-4-iodo-5-methylpyridine in EXAMPLE 307A.
Example 341C
2-(1H-indol-5-yloxy)-4-(4-((5-tert-butyl-4'-chlorobiphenyl-2-yl)methyl)pip-
erazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 341B for EXAMPLE
1D in EXAMPLE 1E.
Example 341D
4-{4-[(5-tert-butyl-4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2--
(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]ph-
enyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 341C for EXAMPLE
26C in EXAMPLE 177. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.22, (s, 1H), 11.16 (s, 1H),
8.62 (t, 1H), 8.58 (d, 1H), 7.79 (dd, 1H), 7.53 (d, 1H), 7.34-7.44
(m, 8H), 7.18 (s, 1H), 7.14 (d, 1H), 7.09 (d, 1H), 6.86 (dd, 1H),
6.67 (dd, 1H), 6.39 (s, 1H), 6.17 (d, 1H), 3.85 (dd, 2H), 3.24-3.30
(m, 6H), 3.04 (s, 4H), 2.29 (s, 4H), 1.86-1.91 (m, 1H), 1.60-1.63
(m, 2H), 1.28 (s, 9H).
Example 342
4-{4-[(5-tert-butyl-4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2--
(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]s-
ulfonyl}benzamide
This example was prepared by substituting EXAMPLE 341C for EXAMPLE
26C and EXAMPLE 279A for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.25, (br s, 1H),
11.16 (s, 1H), 8.40 (d, 1H), 8.06 (dd, 1H), 7.52 (d, 1H), 7.35-7.46
(m, 8H), 7.19 (s, 1H), 7.15 (d, 1H), 6.85 (dd, 1H), 6.66 (dd, 1H),
6.39 (s, 1H), 6.17 (d, 1H), 4.08 (d, 2H), 3.88 (dd, 2H), 3.05 (s,
4H), 2.32 (s, 4H), 1.64 (dd, 2H), 1.32-1.37 (m, 2H), 1.28 (s,
9H).
Example 343
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phen-
yl}sulfonyl)benzamide
Example 343A
3-nitro-4-(2,2,2-trifluoroethylamino)benzenesulfonamide
This example was prepared by substituting 2,2,2-trifluoroethanamine
for (tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 1F.
Example 343B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phen-
yl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 343A for EXAMPLE
1F and EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 10.98 (s, 1H), 8.41 (m,
2H), 7.75 (dd, 1H), 7.54 (d, 1H), 7.34 (d, 2H), 7.28 (m, 2H), 7.06
(m, 3H), 6.93 (m, 1H), 6.70 (dd, 1H), 6.53 (dd, 1H), 6.30 (m, 1H),
6.14 (d, 1H), 4.32 (m, 2H), 2.93 (m, 4H), 2.71 (s, 2H), 2.16 (m,
6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 344
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phen-
yl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 343A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.05 (s, 1H), 8.40 (m, 2H), 7.77 (dd, 1H), 7.60 (d, 1H),
7.34 (d, 2H), 7.18 (m, 1H), 7.12 (d, 1H), 7.04 (m, 3H), 6.88 (t,
1H), 6.58 (dd, 1H), 6.22 (m, 3H), 4.33 (m, 2H), 2.93 (m, 4H), 2.71
(s, 2H), 2.16 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.93 (s,
6H).
Example 345
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]c-
arbonyl}phenyl)sulfonyl]benzamide
Example 345A
3-sulfamoyl-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide
This example was prepared by substituting 3-sulfamoylbenzoic acid
for 4-sulfamoylbenzoic acid in EXAMPLE 308A.
Example 345B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]c-
arbonyl}phenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 345A for EXAMPLE
1F and EXAMPLE 26C for EXAMPLE 1E in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.28 (br s, 1H), 11.18 (s,
1H), 8.75 (t, 1H), 8.41 (m, 1H), 8.10 (d, 1H), 8.01 (d, 1H), 7.60
(t, 1H), 7.48 (d, 1H), 7.41 (m, 2H), 7.33 (d, 2H), 7.23 (d, 1H),
7.03 (d, 2H), 6.88 (dd, 1H), 6.83 (dd, 1H), 6.42 (t, 1H), 6.11 (d,
1H), 3.83 (dd, 2H), 3.19 (m, 4H), 3.02 (m, 4H), 2.73 (m, 2H), 2.16
(m, 6H), 1.94 (br s, 2H), 1.80 (m, 1H), 1.58 (dd, 2H), 1.37 (t,
2H), 1.24 (m, 2H), 0.92 (s, 6H).
Example 346
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-i-
ndol-5-yloxy)benzamide
Example 346A
(R)-4-((1,4-dioxan-2-yl)methoxy)-3-nitrobenzenesulfonamide
The racemic mixture of EXAMPLE 297A was resolved on a SFC chiral AD
column to provide the title compound.
Example 346B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-in-
dol-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 175F by
replacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE
346A, respectively. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.16 (s, 2H), 8.39 (d, 1H),
8.06 (dd, 1H), 7.51 (d, 1H), 7.38-7.43 (m, 3H), 7.34 (d, 2H), 7.15
(d, 1H), 7.04 (d, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.39 (s, 1H),
6.15 (d, 1H), 4.20-4.28 (m, 2H), 3.85-3.91 (m, 1H), 3.82 (dd, 1H),
3.74-3.78 (m, 1H), 3.59-3.69 (m, 2H), 3.40-3.51 (m, 2H), 3.05 (s,
4H), 2.78 (s, 2H), 2.23 (s, 4H), 2.14 (s, 2H), 1.95 (s, 2H), 1.38
(t, 2H), 0.92 (s, 6H).
Example 347
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-in-
dol-5-yloxy)benzamide
Example 347A
(S)-4-((1,4-dioxan-2-yl)methoxy)-3-nitrobenzenesulfonamide
The racemic mixture of EXAMPLE 297A was resolved on a SFC chiral AD
column to provide the title compound.
Example 347B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-in-
dol-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 175F by
replacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE
347A, respectively. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.16 (s, 2H), 8.39 (d, 1H),
8.06 (dd, 1H), 7.51 (d, 1H), 7.38-7.43 (m, 3H), 7.34 (d, 2H), 7.15
(d, 1H), 7.04 (d, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.39 (s, 1H),
6.15 (d, 1H), 4.20-4.28 (m, 2H), 3.85-3.91 (m, 1H), 3.82 (dd, 1H),
3.74-3.78 (m, 1H), 3.59-3.69 (m, 2H), 3.40-3.51 (m, 2H), 3.05 (s,
4H), 2.78 (s, 2H), 2.23 (s, 4H), 2.14 (s, 2H), 1.95 (s, 2H), 1.38
(t, 2H), 0.92 (s, 6H).
Example 348
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifl-
uoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
Example 348A
4-(3-morpholinopropylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide
This example was prepared by substituting EXAMPLE 159C for
4-fluoro-3-nitrobenzenesulfonamide and 3-morpholinopropan-1-amine
for (tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 348B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifl-
uoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
5-yloxy)-N-({4-(methylamino)-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl-
)benzamide
This example was prepared by substituting EXAMPLE 348A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.17 (s, 1H), 8.17 (d, 1H), 7.91 (dd, 1H), 7.49 (d, 1H),
7.40 (m, 3H), 7.33 (d, 2H), 7.15 (d, 1H), 7.03 (m, 3H), 6.85 (dd,
1H), 6.64 (dd, 1H), 6.40 (s, 1H), 6.13 (d, 1H), 3.59 (m, 4H), 3.38
(m, 4H), 3.02 (m, 4H), 2.72 (s, 2H), 2.40 (m, 6H), 2.15 (m, 6H),
1.95 (s, 2H), 1.73 (m, 2H), 0.92 (s, 6H).
Example 349
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifl-
uoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
26C and EXAMPLE 348A for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.25 (s, 1H), 11.08
(m, 1H), 8.12 (d, 1H), 7.81 (dd, 1H), 7.52 (d, 1H), 7.36 (m, 3H),
7.28 (m, 1H), 7.19 (d, 1H), 7.04 (d, 2H), 6.98 (m, 2H), 6.69 (dd,
1H), 6.44 (d, 1H), 6.25 (m, 2H), 3.60 (m, 4H), 3.38 (m, 2H), 3.03
(m, 4H), 2.73 (s, 2H), 2.43 (m, 6H), 2.16 (m, 6H), 1.95 (s, 2H),
1.73 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 350
N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl-
)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 325A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.19 (s, 1H), 11.02 (s, 1H), 8.47 (d, 1H), 8.07 (d, 1H),
7.55 (d, 1H), 7.39 (m, 5H), 7.25 (d, 1H), 7.03 (d, 2H), 6.89 (dd,
1H), 6.65 (dd, 1H), 6.42 (s, 1H), 6.11 (d, 1H), 3.82 (dd, 2H), 3.31
(m, 2H), 3.24 (m, 2H), 3.03 (m, 4H), 2.72 (s, 2H), 2.15 (m, 6H),
1.94 (s, 2H), 1.89 (m, 1H), 1.54 (m, 2H), 1.38 (t, 2H), 1.17 (m,
2H), 0.92 (s, 6H).
Example 351
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-[(triflu-
oromethyl)sulfonyl]phenyl}sulfonyl)benzamide
Example 351A
4-(2-morpholinoethylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide
This example was prepared by substituting EXAMPLE 159C for
4-fluoro-3-nitrobenzenesulfonamide and 2-morpholinoethanamine for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 351B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-[(triflu-
oromethyl)sulfonyl]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 351A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.22 (s, 1H), 11.17 (s, 1H), 8.17 (d, 1H), 7.92 (dd, 1H),
7.61 (s, 1H), 7.48 (d, 1H), 7.40 (m, 2H), 7.33 (d, 2H), 7.15 (d,
1H), 7.03 (d, 2H), 6.93 (d, 1H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.40
(s, 1H), 6.13 (m, 1H), 3.57 (m, 4H), 3.35 (m, 2H), 3.02 (m, 4H),
2.72 (s, 2H), 2.58 (t, 2H), 2.42 (m, 4H), 2.15 (m, 6H), 1.95 (s,
2H), 1.37 (m, 2H), 0.92 (s, 6H).
Example 352
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}su-
lfonyl)-2-(1H-indol-5-yloxy)benzamide
Example 352A
5-cyano-6-((tetrahydro-2H-pyran-4-yl)methylamino)pyridine-3-sulfonamide
This example was prepared by substituting EXAMPLE 325A for EXAMPLE
329B in EXAMPLE 333A.
Example 352B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}su-
lfonyl)-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 352A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.18 (s, 1H), 8.65 (d, 1H), 8.27 (d, 1H), 8.15 (s, 1H),
7.56 (d, 1H), 7.41 (m, 2H), 7.34 (d, 2H), 7.22 (d, 1H), 7.04 (d,
2H), 6.88 (dd, 1H), 6.65 (dd, 1H), 6.41 (m, 1H), 6.12 (d, 1H), 3.82
(dd, 2H), 3.33 (m, 2H), 3.24 (t, 2H), 3.04 (m, 4H), 2.75 (s, 2H),
2.16 (m, 6H), 1.95 (s, 2H), 1.89 (m, 1H), 1.55 (m, 2H), 1.38 (t,
2H), 1.19 (m, 2H), 0.91 (s, 6H).
Example 353
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)oxy]-3-nitrophen-
yl}sulfonyl)benzamide
Example 353A
4-(1-methylpiperidin-4-yloxy)-3-nitrobenzenesulfonamide
To a mixture of 1-methylpiperidin-4-ol (0.542 g) in tetrahydrofuran
(10 mL) at 0.degree. C. was added NaH (60% in mineral oil) (0.753
g). After stirring for 15 minutes,
4-fluoro-3-nitrobenzenesulfonamide (1.036 g) was added as a
solution in tetrahydrofuran (10 mL). The reaction was removed from
the ice bath and allowed to warm to room temperature. After 1 hour,
the reaction was poured into water and the pH adjusted to -7 with
1N aqueous HCl.
The reaction was extracted with dichloromethane (3.times.100 mL),
washed with brine, dried over magnesium sulfate, filtered, and
concentrated. The product was suspended in dichloromethane (mL),
sonicated and then filtered to give the title compound.
Example 353B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)oxy]-3-nitrophen-
yl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 353A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide) .delta. 11.03 (s, 1H), 8.21 (d, 1H), 7.87
(dd, 1H), 7.55 (d, 1H), 7.33 (dd, 4H), 7.25 (d, 1H), 7.04 (d, 2H),
6.98 (d, 1H), 6.73 (dd, 1H), 6.56 (d, 1H), 6.33 (s, 1H), 6.14 (d,
1H), 4.79 (s, 1H), 2.96 (s, 6H), 2.72 (s, 2H), 2.57 (s, 3H), 2.18
(s, 6H), 1.94 (m, 6H), 1.39 (m, 2H), 0.92 (s, 6H).
Example 354
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitro-
phenyl}sulfonyl)benzamide
Example 354A
4-((1-methylpiperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide
This example was prepared by substituting
(1-methylpiperidin-4-yl)methanol for 1-methylpiperidin-4-ol in
EXAMPLE 353A.
Example 354B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitro-
phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 354A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide) .delta. 11.01 (s, 1H), 8.19 (d, 1H), 7.87
(dd, 1H), 7.55 (d, 1H), 7.39-7.26 (m, 4H), 7.16 (d, 1H), 7.08-7.01
(m, 2H), 6.96 (d, 1H), 6.72 (dd, 1H), 6.54 (d, 1H), 6.32 (s, 1H),
6.14 (d, 1H), 4.05 (d, 2H), 2.95 (s, 4H), 2.89-2.59 (m, 7H), 2.17
(s, 6H), 2.00-1.78 (m, 5H), 1.53 (s, 2H), 1.37 (m, 2H), 0.92 (s,
6H).
Example 355
4-(4-{[4-(4-chlorophenyl)-1-(3-hydroxypropyl)-1,2,5,6-tetrahydropyridin-3--
yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro--
2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
Example 355A
tert-butyl
4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylate
To N,N-dimethylformamide (3.87 mL) at 0.degree. C., phosphorus
oxychloride (3.73 mL) was added dropwise, maintaining the
temperature below 5.degree. C. The resulting mixture was diluted
with dichloromethane (15 mL) and stirred at room temperature for
1.5 hours. The reaction was then cooled in an ice bath. tert-Butyl
4-oxopiperidine-1-carboxylate (4.98 g) was added as a solution in
dichloromethane (20 mL) and the reaction was stirred at room
temperature for 1 hour. The reaction mixture was poured over ice
and solid sodium acetate, stirred for 15 minutes, and extracted
with dichloromethane. The extracts were washed thoroughly with
water and with brine, dried over MgSO.sub.4, filtered, and
concentrated to obtain the title compound.
Example 355B
tert-butyl
4-(4-chlorophenyl)-3-formyl-5,6-dihydropyridine-1(2H)-carboxyla-
te
EXAMPLE 355A (6.14 g), 4-chlorophenylboronic acid (4.10 g) and
palladium(II) acetate (0.112 g) were combined in water to give a
suspension. Potassium carbonate (8.98 g) and tetrabutylammonium
bromide (4.03 g) were added. The resulting mixture was stirred at
45.degree. C. overnight, cooled, and the reaction mixture was
diluted with ethyl acetate (200 mL) in order to dissolve any
insoluble material, then washed thoroughly with water, dried over
MgSO.sub.4, filtered, and concentrated. The crude material was
purified by flash chromatography eluting with a gradient of 10%
ethyl acetate/hexanes to 40% ethyl acetate/hexanes.
Example 355C
tert-butyl
3-((4-(3-(1H-indol-4-yloxy)-4-(methoxycarbonyl)phenyl)piperazin-
-1-yl)methyl)-4-(4-chlorophenyl)-5,6-dihydropyridine-(2H)-carboxylate
This example was prepared by substituting EXAMPLE 355B for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 355D
methyl
2-(1H-indol-4-yloxy)-4-(4-((4-(4-chlorophenyl)-1,2,5,6-tetrahydropy-
ridin-3-yl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 355C for EXAMPLE
1A in EXAMPLE 1B.
Example 355E
methyl
2-(1H-indol-4-yloxy)-4-(4-((4-(4-chlorophenyl)-1-(3-hydroxypropyl)--
1,2,5,6-tetrahydropyridin-3-yl)methyl)piperazin-1-yl)benzoate
EXAMPLE 355D (539 mg), 3-bromopropan-1-ol (83 mg) and triethylamine
(0.42 mL) were combined in acetonitrile. The mixture was heated to
60.degree. C. overnight, concentrated and then triturated with
ether and filtered to give the title compound.
Example 355F
2-(1H-indol-4-yloxy)-4-(4-((4-(4-chlorophenyl)-1-(3-hydroxypropyl)-1,2,5,6-
-tetrahydropyridin-3-yl)methyl)piperazin-1-yl)benzoic acid
This example was prepared by substituting EXAMPLE 355E for EXAMPLE
1D in EXAMPLE 1E.
Example 355G
4-(4-{[4-(4-chlorophenyl)-1-(3-hydroxypropyl)-1,2,5,6-tetrahydropyridin-3--
yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro--
2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 355F for EXAMPLE
1E in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.17 (s, 1H), 8.49 (br s, 1H), 8.44 (s, 1H), 7.69 (dd,
1H), 7.56 (d, 1H), 7.40 (d, 1H), 7.24 (m, 1H), 7.13 (m, 3H), 6.98
(m, 1H), 6.94 (t, 1H), 6.86 (dd, 1H), 6.36 (m, 1H), 6.24 (m, 2H),
3.84 (dd, 2H), 3.47 (t, 2H), 3.26 (m, 4H), 2.99 (br s, 4H), 2.80
(m, 3H), 2.44 (m, 2H), 2.21 (m, 4H), 1.86 (m, 1H), 1.73 (m, 2H),
1.62 (m, 2H), 1.26 (m, 5H), 1.17 (m, 2H).
Example 356
benzyl
4-({[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]-
methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzoyl]amino}sulfonyl)-2-nitro-
phenyl]amino}methyl)piperidine-1-carboxylate
Example 356A
benzyl
4-((2-nitro-4-sulfamoylphenylamino)methyl)piperidine-1-carboxylate
The title compound was prepared as described in EXAMPLE 1F by
replacing (tetrahydro-2H-pyran-4-yl)methanamine with benzyl
4-(aminomethyl)piperidine-1-carboxylate.
Example 356B
benzyl
4-({[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]-
methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzoyl]amino}sulfonyl)-2-nitro-
phenyl]amino}methyl)piperidine-1-carboxylate
The title compound was prepared as described in EXAMPLE 175F by
replacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE
356A, respectively. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.17 (s, 2H), 8.63 (t, 1H),
8.58 (d, 1H), 7.79 (dd, 1H), 7.51 (d, 1H), 7.30-7.42 (m, 8H), 7.16
(d, 1H), 7.10 (d, 1H), 7.03 (d, 2H), 6.86 (dd, 1H), 6.65 (dd, 1H),
6.39 (s, 1H), 6.14 (d, 1H), 5.07 (s, 2H), 4.02 (d, 2H), 3.29-3.34
(m, 2H), 3.03 (s, 4H), 2.70-2.88 (m, 4H), 2.08-2.23 (m, 6H), 1.94
(s, 2H), 1.81-1.89 (m, 1H), 1.71 (d, 2H), 1.37 (t, 2H), 1.07-1.16
(m, 2H), 0.92 (s, 6H).
Example 357
N-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)benzamide
Example 357A
3-cyano-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide
To (tetrahydro-2H-pyran-4-yl)methanol (0.206 g) in tetrahydrofuran
(5 mL) was added sodium hydride (0.284 g) and the reaction stirred
at room temperature for 20 minutes. The reaction was cooled to
0.degree. C. and 3-cyano-4-fluorobenzenesulfonamide (0.355 g) in
tetrahydrofuran (2 mL) was added dropwise and the reaction was
allowed to warm to room temperature. After 3 hours, the reaction
was poured into water, made acidic (pH=1) with 1N HCl and extracted
with dichloromethane (2.times.75 mL). The organics were combined,
washed with brine (50 mL), dried over magnesium sulfate, filtered
and concentrated to give the title compound.
Example 357B
5-sulfamoyl-2-((tetrahydro-2H-pyran-4-yl)methoxy)benzamide
A mixture of EXAMPLE 357A (0.455 g) in ethanol (3 mL) and
tetrahydrofuran (1 mL) was added to hydrogen peroxide (30%, 2 mL)
followed by NaOH (1.024 ml) and heated to 35.degree. C. for 3
hours. The mixture was poured into dichloromethane (50 mL) and 1N
aqueous HCl (25 mL), upon which a precipitate formed. The title
compound was extracted into dichloromethane (3.times.50 mL). The
organic layer contained a solid which was collected by filtration
and dried to give the title compound.
Example 357C
N-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 357B for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, CDCL3) .delta. 10.35 (s, 1H), 8.80 (d, 1H), 8.35 (dd, 2H),
7.91 (d, 1H), 7.44 (d, 2H), 7.39 (d, 1H), 7.34-7.29 (m, 1H), 7.22
(d, 2H), 7.07 (d, 1H), 6.99 (dd, 1H), 6.93-6.87 (m, 2H), 6.58 (s,
1H), 6.48 (dd, 1H), 6.06 (d, 1H), 5.80 (s, 1H), 4.05 (dd, 4H), 3.46
(dd, 2H), 3.03 (s, 4H), 2.73 (s, 2H), 2.19 (m, 7H), 1.96 (s, 2H),
1.74 (m, 2H), 1.43 (m, 4H), 0.93 (s, 6H).
Example 358
4-(4-{[4'-chloro-5-(trifluoromethyl)-,
1'-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro--
4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzami-
de
This example was prepared by substituting EXAMPLE 339C for EXAMPLE
26C and EXAMPLE 173C for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.11 (s, 1H), 8.54
(d, 1H), 8.19 (d, 1H), 7.78 (dd, 1H), 7.71-7.74 (m, 2H), 7.44-7.54
(m, 7H), 7.36-7.38 (m, 2H), 7.04-7.07 (m, 2H), 6.87 (dd, 1H), 6.63
(dd, J=8.7, 1.68 Hz, 1H), 6.36 (s, 1H), 6.16 (d, 1H), 3.93 (dd,
2H), 3.75 (br s, 2H), 3.41 (s, 2H), 3.01-3.07 (m, 6H), 2.66-2.68
(m, 2H), 2.30 (s, 4H), 1.77-1.80 (m, 2H), 1.47-1.53 (m, 2H).
Example 359
4-{4-[(5-tert-butyl-4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2--
(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-y-
l)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 341C for EXAMPLE
26C and EXAMPLE 173C for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.11, (s, 1H), 8.53
(t, 1H), 8.19 (d, 1H), 7.76 (dd, 1H), 7.53 (d, 1H), 7.36-7.44 (m,
8H), 7.19 (s, 1H), 7.04-7.07 (m, 2H), 6.81 (dd, 1H), 6.63 (dd, 1H),
6.36 (s, 1H), 6.17 (d, 1H), 3.93 (dd, 2H), 3.74-3.75 (m, 2H),
3.01-3.07 (m, 6H), 2.64-2.67 (m, 2H), 2.29 (s, 4H), 1.99-2.03 (m,
4H), 1.77-1.80 (m, 2H), 1.65-1.67 (m, 2H), 1.28 (s, 9H).
Example 360
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-methyl-1H-imidazol-5-yl)methyl]amino-
}-3-nitrophenyl)sulfonyl]benzamide
This example was prepared by substituting
(1-methyl-1H-imidazol-5-yl)methanamine for
(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in
EXAMPLE 187B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.17 (s, 1H), 8.81 (t, 1H), 8.59 (d, 1H), 7.83 (dd, 1H),
7.64 (s, 1H), 7.50 (d, 1H), 7.39-7.42 (m, 2H), 7.33 (d, 2H),
7.16-7.17 (m, 2H), 7.03 (d, 2H), 6.98 (s, 1H), 6.85 (dd, 1H), 6.63
(dd, 1H), 6.40 (s, 1H), 6.13 (d, 1H), 4.66 (d, 2H), 3.64 (s, 3H),
3.02 (s, 4H), 2.72 (s, 2H), 2.12-2.16 (m, 6H), 1.94 (s, 2H), 1.37
(t, 2H), 0.92 (s, 6H).
Example 361
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylsulfonyl)phenyl]sulfonyl}b-
enzamide
Example 361A
4-(morpholinosulfonyl)benzenesulfonamide
This example was prepared by substituting
4-(morpholinosulfonyl)benzene-1-sulfonyl chloride for EXAMPLE 66D
in EXAMPLE 66E.
Example 361B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylsulfonyl)phenyl]sulfonyl}b-
enzamide
This example was prepared by substituting EXAMPLE 361A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 10.99 (s, 1H), 7.76 (d, 2H), 7.57 (d, 1H), 7.46 (d, 2H),
7.35 (d, 2H), 7.28 (m, 2H), 7.05 (d, 2H), 6.89 (d, 1H), 6.70 (dd,
1H), 6.57 (dd, 1H), 6.31 (m, 1H), 6.21 (m, 1H), 3.60 (m, 4H), 2.97
(m, 4H), 2.79 (m, 4H), 2.72 (s, 2H), 2.18 (m, 6H), 1.96 (s, 2H),
1.39 (t, 2H), 0.93 (s, 6H).
Example 362
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-
-2-(1H-indol-5-yloxy)benzamide
Example 362A
4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonamide
This example was prepared by substituting
4-aminothiomorpholine-1,1-dioxide for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 362B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-
-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 362A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.19 (s, 1H), 11.17 (s, 1H), 9.64 (s, 1H), 8.55 (d, 1H),
7.86 (m, 1H), 7.78 (m, 1H), 7.51 (d, 1H), 7.40 (m, 2H), 7.33 (d,
2H), 7.16 (s, 1H), 7.03 (d, 2H), 6.86 (dd, 1H), 6.64 (dd, 1H), 6.39
(s, 1H), 6.13 (d, 1H), 3.50 (m, 4H), 3.17 (m, 4H), 3.02 (m, 4H),
2.72 (s, 2H), 2.15 (m, 6H), 1.94 (s, 2H), 1.37 (t, 2H), 0.91 (s,
6H).
Example 363
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nit-
rophenyl}sulfonyl)benzamide
Example 363A
tert-butyl cis-4-morpholinocyclohexylcarbamate
To a mixture of morpholine (4.08 ml) and tert-butyl
4-oxocyclohexylcarbamate (10 g) stirred for 24 hours at room
temperature in titanium(IV) isopropoxide (27.5 ml), methanol (10
ml) was added followed by careful addition of sodium borohydride
(3.55 g). The reaction mixture was quenched with water, extracted
with ether (2.times.100 mL), dried over magnesium sulfate, filtered
and concentrated. The crude product was purified by FC (silica gel
200 g, 30%-100% acetone/hexanes) providing two products, the title
compound and trans 4-morpholinocyclohexylcarbamate.
Example 363B
cis-4-morpholinocyclohexanamine bis(2,2,2-trifluoroacetate)
This example was prepared by substituting EXAMPLE 363A for EXAMPLE
1A in EXAMPLE 1B.
Example 363C
4-(cis-4-morpholinocyclohexylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting EXAMPLE 363B for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 363D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[cis-(4-morpholin-4-ylcyclohexyl)amino]-3-
-nitrophenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 363C for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (500
MHz, pyridine-d.sub.5) .delta. 12.28 (s, 1H), 9.31 (d, 1H), 8.65
(d, 1H), 8.34 (dd, 1H), 8.17 (d, 1H), 7.53-7.57 (m, 2H), 7.40-7.47
(m, 3H), 7.03-7.12 (m, 3H), 6.89 (d, 1H), 6.72 (dd, 1H), 6.62 (s,
1H), 6.54 (d, 1H), 3.69-3.75 (m, 4H), 3.67 (s, 1H), 3.00-3.07 (m,
4H), 2.75 (s, 2H), 2.41-2.47 (m, 4H), 2.24 (t, 2H), 2.07-2.16 (m,
5H), 1.97 (s, 2H), 1.76-1.85 (m, 2H), 1.54-1.65 (m, 6H), 1.38 (t,
2H), 0.93 (s, 6H).
Example 364
N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-
-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl-
)-2-(1H-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
26C and EXAMPLE 329B for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.17 (s, 1H), 8.65
(d, 1H), 8.33 (s, 1H), 7.58 (d, 1H), 7.35 (d, 2H), 7.24 (t, 1H),
7.07 (m, 3H), 6.89 (m, 1H), 6.67 (dd, 1H), 6.27 (m, 3H), 4.29 (d,
2H), 3.88 (dd, 2H), 3.35 (m, 4H), 3.09 (m, 4H), 2.88 (m, 2H), 2.34
(m, 2H), 2.17 (s, 2H), 2.06 (m, 1H), 1.98 (m, 2H), 1.65 (m, 2H),
1.36 (m, 4H), 0.93 (s, 6H).
Example 365
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-{[6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-5-
-(1,3-thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamide
This example was prepared by substituting EXAMPLE 325B for EXAMPLE
329B in EXAMPLE 331A. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.22 (s, 1H), 9.76 (t, 1H),
9.12 (m, 1H), 8.50 (d, 1H), 8.26 (d, 1H), 8.02 (d, 1H), 7.87 (d,
1H), 7.58 (d, 1H), 7.38 (d, 2H), 7.23 (t, 1H), 7.15 (d, 1H), 7.08
(d, 2H), 6.96 (m, 1H), 6.74 (dd, 1H), 6.47 (d, 1H), 6.33 (s, 1H),
6.22 (s, 1H), 3.86 (dd, 2H), 3.52 (t, 6H), 3.29 (m, 4H), 2.99 (m,
2H), 2.74 (m, 2H), 2.18 (s, 2H), 2.01 (s, 2H), 1.88 (m, 1H), 1.62
(m, 2H), 1.45 (t, 2H), 1.28 (m, 2H), 0.94 (s, 6H).
Example 366
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-(1H-indol-4-yloxy)benzamide
Example 366A
3-cyano-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide
3-Cyano-4-fluorobenzenesulfonamide (500 mg),
(tetrahydropyran-4-yl)methylamine (288 mg), and
N,N-diisopropylethylamine (1.3 mL) were heated at 80.degree. C. in
tetrahydrofuran (15 mL) overnight. The mixture was diluted with
ethyl acetate, washed with NaHCO.sub.3 solution and brine, and
dried (Na.sub.2SO.sub.4), filtered and concentrated. The product
was triturated from ethyl acetate.
Example 366B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-(1H-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
26C and EXAMPLE 366A for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.30 (s, 1H), 11.08
(m, 1H), 7.81 (d, 1H), 7.63 (dd, 1H), 7.55 (d, 1H), 7.32 (m, 3H),
7.22 (d, 1H), 7.17 (m, 1H), 7.02 (m, 3H), 6.79 (d, 1H), 6.71 (dd,
1H), 6.47 (d, 1H), 6.28 (m, 2H), 3.84 (dd, 2H), 3.25 (t, 2H), 3.13
(t, 2H), 3.05 (m, 4H), 2.73 (s, 2H), 2.15 (m, 6H), 1.95 (s, 2H),
1.82 (m, 1H), 1.59 (m, 2H), 1.38 (t, 2H), 1.20 (m, 2H), 0.92 (s,
6H).
Example 367
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 366A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.20 (s, 1H), 10.99 (s, 1H), 7.94 (d, 1H), 7.74 (dd, 1H),
7.53 (d, 1H), 7.44 (d, 1H), 7.41 (m, 1H), 7.33 (d, 2H), 7.21 (m,
2H), 7.04 (d, 2H), 6.89 (dd, 1H), 6.82 (d, 1H), 6.66 (dd, 1H), 6.42
(s, 1H), 3.83 (dd, 2H), 3.25 (t, 2H), 3.13 (t, 2H), 3.03 (m, 4H),
2.72 (s, 2H), 2.14 (m, 6H), 1.94 (s, 2H), 1.83 (m, 1H), 1.57 (m,
2H), 1.37 (m, 2H), 1.21 (m, 2H), 0.92 (s, 6H).
Example 368
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(3,3-dimethylbutyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-
-5-yloxy)benzamide
This example was prepared by substituting 3,3-dimethylbutylamine
for 1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.
Example 369
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(1S)-1-(hydroxymethyl)-3-methylbutyl]amino}-3-nitrophenyl)su-
lfonyl]-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting L-leucinol for
1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.
Example 370
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(2R)-tetrahydrofuran-2-ylmethyl-
]amino}phenyl)sulfonyl]benzamide
This example was prepared by substituting
(R)-(-)-tetrahydrofurfurylamine for
1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.
Example 371
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(1R)-1-(hydroxymethyl)-2-methylpropyl]amino}-3-nitrophenyl)s-
ulfonyl]-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting D-valinol for
1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.
Example 372
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methoxyphenyl)amino]-3-nitrophenyl}su-
lfonyl)benzamide
This example was prepared by substituting 4-anisidine for
1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.
Example 373
N-[(4-{[2-(1,3-benzodioxol-5-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]-4-(4--
{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-
-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting
2-benzo[1,3]dioxol-5-yl-ethylamine for
1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.
Example 374
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(2-oxopyrrolidin-1-yl)propyl]-
amino}phenyl)sulfonyl]benzamide
This example was prepared by substituting
1-(3-amino-propyl)-pyrrolidin-2-one for
1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.
Example 375
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-hydroxyphenyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-
-yloxy)benzamide
This example was prepared by substituting 4-aminophenol for
1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.
Example 376
N-{[4-({2-[4-(aminosulfonyl)phenyl]ethyl}amino)-3-nitrophenyl]sulfonyl}-4--
(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1--
yl)-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting
4-(2-aminoethyl)benzenesulfonamide for
1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.
Example 377
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[3-(1H-imidazol-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2--
(1H-indol-5-yloxy)benzamide
This example was prepared by substituting
1-(3-aminopropyl)imidazole for
1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.
Example 378
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1S)-1-phenylethyl]amino}phenyl-
)sulfonyl]benzamide
This example was prepared by substituting
(S)-(-)-1-phenylethylamine for
1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.
Example 379
N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulf-
onyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-5-yloxy)benzamide
Example 379A
2-chloro-5-fluoro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonam-
ide
2-Chloro-4,5-difluorobenzenesulfonamide (0.683 g),
(tetrahydro-2H-pyran-4-yl)methanamine (0.346 g),
N,N-diisopropylethylamine (0.681 ml) and dioxane (10 ml) were
heated at 65.degree. C. for 2.5 days. Additional
(tetrahydro-2H-pyran-4-yl)methanamine (0.346 g) and
N,N-diisopropylethylamine (0.681 ml) were added and heating was
continued at 70.degree. C. for 1.5 days. The reaction mixture was
concentrated and column chromatographed on silica gel with 0-3%
methanol in dichloromethane as eluent. The obtained solid was
triturated with dichloromethane to give the title compound.
Example 379B
N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulf-
onyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 379A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 11.23 (s, 1H), 11.02
(s, 1H), 7.61 (m, 2H), 7.44 (m, 2H), 7.33 (d, 2H), 7.30 (m, 1H),
7.03 (d, 2H), 6.95 (m, 1H), 6.88 (m, 2H), 6.67 (dd, 1H), 6.44 (m,
1H), 6.09 (d, 1H), 3.82 (dd, 2H), 3.22 (m, 2H), 3.03 (m, 6H), 2.72
(m, 2H), 2.14 (m, 6H), 1.94 (m, 2H), 1.81 (m, 1H), 1.61 (m, 2H),
1.37 (t, 2H), 1.18 (m, 2H), 0.91 (s. 6H).
Example 380
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitrop-
henyl)sulfonyl]benzamide
Example 380A
4-(2-(2-methoxyethoxy)ethylthio)-3-nitrobenzenesulfonamide
In a 100 mL round-bottomed flask was added sodium hydride (0.6 g)
in tetrahydrofuran (10 ml) to give a suspension.
2-(2-Methoxyethoxy)ethanethiol (1 g) was added slowly. After the
mixture stirred for 30 minutes, 4-fluoro-3-nitrobenzenesulfonamide
(1.616 g) in 10 ml tetrahydrofuran was added slowly. After the
mixture stirred overnight, water was added slowly, and ethyl
acetate (20 ml.times.3) was used to extract the product. The
combined organic layers were dried over Na.sub.2SO.sub.4. After the
mixture was filtered and concentrated, the crude product was added
to a silica gel column and purified eluting with 0-10% methanol in
dichloromethane.
Example 380B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitrop-
henyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 380A for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 10.99 (s, 1H), 8.42 (s, 1H), 7.75 (d, 1H), 7.56 (d, 1H),
7.34 (m, 5H), 7.05 (d, 2H), 6.90 (d, 1H), 6.69 (dd, 1H), 6.55 (dd,
1H), 6.30 (m, 1H), 6.17 (d, 1H), 3.67 (t, 2H), 3.54 (m, 2H), 3.43
(m, 2H), 3.21 (m, 5H), 2.95 (m, 4H), 2.71 (s, 2H), 2.17 (m, 6H),
1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 381
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitrop-
henyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 380A for EXAMPLE
1F and EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.06 (s, 1H), 8.37 (d,
1H), 7.80 (dd, 1H), 7.61 (d, 1H), 7.45 (d, 1H), 7.34 (d, 2H), 7.18
(t, 1H), 7.04 (m, 3H), 6.87 (t, 1H), 6.60 (dd, 1H), 6.22 (m, 3H),
3.68 (t, 2H), 3.55 (m, 2H). 3.43 (m. 2H), 3.22 (m. 5H), 2.94 (m,
4H), 2.72 (s, 2H), 2.16 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92
(s, 6H).
Example 382
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylsulfonyl)phenyl]sulfonyl}benzamide
This example was prepared by substituting
4-(methylamino)-3-nitrobenzenesulfonamide for EXAMPLE 1F in EXAMPLE
177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.17
(s, 1H), 8.05 (m, 4H), 7.51 (d, 1H), 7.38 (m, 4H), 7.14 (m, 1H),
7.04 (d, 2H), 6.85 (d, 1H), 6.64 (dd, 1H), 6.40 (m, 1H), 6.17 (d,
1H), 3.27 (s, 3H), 3.05 (m, 4H), 2.79 (m, 2H), 2.21 (m, 6H), 1.96
(s, 2H), 1.39 (t, 2H), 0.92 (s, 6H).
Example 383
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(methylsulfonyl)phenyl]sulfonyl}benzamide
This example was prepared by substituting
4-(methylamino)-3-nitrobenzenesulfonamide for EXAMPLE 1F and
EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.26 (s, 1H), 7.96 (m, 4H),
7.54 (d, 1H), 7.35 (d, 2H), 7.30 (m, 1H), 7.18 (d, 1H), 7.05 (d,
2H), 6.97 (t, 1H), 6.70 (dd, 1H), 6.37 (d, 1H), 6.30 (m, 2H), 3.25
(s, 3H), 3.08 (m, 4H), 2.84 (m, 2H), 2.26 (m, 6H), 1.97 (s, 2H),
1.40 (t, 2H), 0.93 (s, 6H).
Example 384
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}-
sulfonyl)-2-(1H-indol-5-yloxy)benzamide
Example 384A
The title compound was prepared as described in EXAMPLE 297A by
replacing (1,4-dioxan-2-yl)methanol with
(2,2-dimethyltetrahydro-2H-pyran-4-yl)methanol.
Example 384B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}-
sulfonyl)-2-(1H-indol-5-yloxy)benzamide
The title compound was prepared as described in EXAMPLE 175F by
replacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE
384A, respectively. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.17 (s, 2H), 8.38 (d, 1H),
8.05 (dd, 1H), 7.51 (d, 1H), 7.31-7.43 (m, 5H), 7.15 (d, 1H), 7.04
(d, 2H), 6.85 (dd, 1H), 6.65 (dd, 1H), 6.40 (s, 1H), 6.15 (d, 1H),
3.98-4.07 (m, 2H), 3.54-3.67 (m, 2H), 3.05 (s, 4H), 2.78 (s, 2H),
2.09-2.31 (m, 7H), 1.95 (s, 2H), 1.56-1.68 (m, 2H), 1.38 (t, 2H),
1.08-1.27 (m, 8H), 0.92 (s, 6H).
Example 385
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-y-
l}sulfonyl)-2-(1H-indol-5-yloxy)benzamide
Example 385A
5-bromo-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamid-
e
This example was prepared by substituting EXAMPLE 306C for
(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 329B.
Example 385B
5-cyano-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamid-
e
This example was prepared by substituting EXAMPLE 385A for EXAMPLE
329B in EXAMPLE 333A.
Example 385C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-y-
l}sulfonyl)-2-(1H-indol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 385B for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.10 (s, 1H). 8.79 (s, 1H), 8.59 (s, 1H), 7.54 (d, 1H),
7.34-7.38 (m, 4H), 7.04-7.06 (m, 3H), 6.79 (dd, 1H), 6.62 (dd, 1H),
6.35 (s, 1H), 6.17 (d, 1H), 4.28 (d, 2H), 3.76-3.79 (m, 2H),
3.56-3.62 (m, 2H), 3.07 (br s, 4H), 2.12-2.17 (m, 4H), 1.96 (s,
2H), 1.80-1.84 (m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).
Example 386
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl-
}-2-(1H-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
26C and EXAMPLE 335A for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.20 (s, 1H), 8.67
(d, 1H), 8.35 (d, 1H), 7.57 (d, 1H), 7.36 (d, 2H), 7.26 (t, 1H),
7.11 (d, 1H), 7.05 (d, 2H), 6.90 (t, 1H), 6.70 (dd, 1H), 6.31 (d,
1H), 6.30 (d, 1H), 6.27 (s, 1H), 4.30 (d, 2H), 3.88 (dd, 2H), 3.35
(m, 2H), 3.12 (br s, 4H), 2.96 (br s, 2H), 2.40 (br s, 4H), 2.16
(br m, 2H), 2.06 (m, 1H), 1.98 (s, 2H), 1.65 (d, 2H), 1.41 (t, 2H),
1.36 (m, 2H), 0.93 (s, 6H).
Example 387
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfony-
l}-2-(1H-indol-4-yloxy)benzamide
Example 387A
5,6-dichloropyridine-3-sulfonamide
This example was prepared by substituting
5,6-dichloropyridine-3-sulfonyl chloride for
5-bromo-6-chloropyridine-3-sulfonyl chloride in EXAMPLE 329A.
Example 387B
5-chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
This example was prepared by substituting EXAMPLE 387A for EXAMPLE
329A in EXAMPLE 329B.
Example 387C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfony-
l}-2-(1H-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
26C and EXAMPLE 387B for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.24 (s, 1H), 8.45
(d, 1H), 8.05 (d, 1H), 7.56 (d, 1H), 7.36 (d, 2H), 7.28 (t, 1H),
7.15 (d, 1H), 7.05 (d, 2H), 6.95 (t, 1H), 6.71 (dd, 1H), 6.39 (d,
1H), 6.30 (d, 1H), 6.27 (s, 1H), 4.26 (d, 2H), 3.88 (dd, 2H), 3.35
(m, 2H), 3.09 (br s, 4H), 2.85 (br s, 2H), 2.30 (br s, 4H), 2.15
(br m, 2H), 2.07 (m, 1H), 1.96 (s, 2H), 1.65 (d, 2H), 1.41 (t, 2H),
1.35 (m, 2H), 0.93 (s, 6H).
Example 388
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-i-
ndol-5-yloxy)benzamide
Example 388A
5-bromo-6-(2-morpholinoethoxy)pyridine-3-sulfonamide
This example was prepared by substituting 2-morpholinoethanol for
(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 329B.
Example 388B
5-cyano-6-(2-morpholinoethoxy)pyridine-3-sulfonamide
This example was prepared by substituting EXAMPLE 388A for EXAMPLE
329B in EXAMPLE 335A.
Example 388C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(H-in-
dol-5-yloxy)benzamide
This example was prepared by substituting EXAMPLE 388B for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.09 (s, 1H), 8.77 (s, 1H), 8.55 (s, 1H), 7.55 (d, 1H),
7.34-7.36 (m, 4H), 7.04-7.06 (m, 3H), 6.78 (dd. 1H), 6.63 (d. 1H),
6.35 (s, 1H), 6.16 (s, 1H), 4.61 (t, 2H), 3.58 (m, 4H), 3.05 (br s,
4H), 2.89 (br s, 4H), 2.65 (br s, 4H), 2.32-2 (br s, 2H), 2.15 (br
s, 2H), 1.96 (s, 2H), 1.39 (t, 2H), 0.92 (s, 6H).
Example 389
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiper-
idin-4-yl)oxy]phenyl}sulfonyl)benzamide
Example 389A
1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ol
Piperidin-4-ol (7.8 g) and dihydro-2H-pyran-4(3H)-one (5.0 g) were
dissolved in titanium(IV) isopropoxide (30 mL) and the reaction was
stirred at room temperature overnight. Methanol (40 mL) was added
and the reaction was cooled to 0.degree.. NaBH.sub.4 (3.8 g) was
added in several portions over one hour. After two hours 1N aqueous
NaOH was added, followed by ethyl acetate addition. After
filtration through celite, the layers were separated, the aqueous
layer was extracted with ethyl acetate, and the combined organic
layers were dried over Na.sub.2SO.sub.4. The crude material was
purified by column chromatography using CH.sub.2Cl.sub.2 with 5-10%
7N NH.sub.3 in methanol.
Example 389B
3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yloxy)benzenesulfonamid-
e
EXAMPLE 389A (370 mg) was dissolved in tetrahydrofuran (10 mL), and
95% NaH (200 mg) was added. After stirring for 10 minutes,
4-fluoro-3-nitrobenzenesulfonamide (420 mg) was added and the
reaction was stirred at room temperature overnight. The reaction
was purified by column chromatography using CH.sub.2Cl.sub.2 with
6-10% 7N NH.sub.3 in methanol, followed by slurrying in diethyl
ether and filtering off the solid product.
Example 389C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiper-
idin-4-yl)oxy]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 389B for EXAMPLE 1F in EXAMPLE 1G, except here 5-7%
methanol in CH.sub.2Cl.sub.2 was used for the chromatography.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.07 (br
s, 1H), 8.27 (s, 1H), 7.92 (d, 1H), 7.55 (d, 1H), 7.33 (m, 5H),
7.04 (m, 3H), 6.77 (dd, 1H), 6.58 (d, 1H), 6.35 (s, 1H), 6.14 (s,
1H), 4.85 (s, 1H), 3.93 (dd, 2H), 3.27 (m, 4H), 2.98 (br m, 7H),
2.72 (s, 2H), 2.16 (m, 6H), 2.04 (m, 2H), 1.95 (s, 2H), 1.84 (m,
4H), 1.55 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Example 390
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitro-
phenyl}sulfonyl)benzamide
Example 390A
4-morpholinobut-2-yn-1-ol
To a mixture of morpholine (4.36 g) in toluene (15 mL) was added
4-chlorobut-2-yn-1-ol (2.09 g) in toluene (5 mL). The mixture was
stirred at 85.degree. C. for three hours. After cooling, the solid
was filtered off. The filtrate was subjected to vacuum distillation
to give the title compound.
Example 390B
4-(4-morpholinobut-2-ynyloxy)-3-nitrobenzenesulfonamide
This example was prepared by substituting EXAMPLE 390A for
(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 279A.
Example 390C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitro-
phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 390B for EXAMPLE
1F in EXAMPLE 177. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.17 (s, 1H), 8.40 (d, 1H), 8.11 (dd, 1H), 7.49-7.53 (m,
2H), 7.39-7.42 (m, 4H), 7.34 (d, 2H), 7.17 (d, 1H), 7.04 (d, J=8.54
Hz, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.40 (s, 1H), 6.14 (d, 1H),
5.15 (s, 2H), 3.52-3.54 (m, 4H), 3.04 (br s, 4H), 2.78 (br s, 2H),
2.37-2.39 (m, 4H), 2.12-2.20 (br s, 6H), 1.95 (s, 2H), 1.38 (t,
2H), 0.92 (s, 6H).
Example 391
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfon-
yl}-2-(1H-indol-4-yloxy)benzamide
Example 391A
6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-((triisopropylsilyl)ethynyl)pyridi-
ne-3-sulfonamide
EXAMPLE 329B (0.176 g), bis(triphenylphosphine)palladium(II)
chloride (0.176 g), copper(I) iodide (0.010 g), dimethylacetamide
(2.5 ml) and triethylamine (0.105 ml) were combined, flushed with
nitrogen and stirred for 2 minutes. (Triisopropyl)acetylene (0.135
ml) was added and the reaction mixture was flushed with nitrogen
again, heated at 60.degree. C. overnight, diluted with ethyl
acetate, washed with water and brine, dried (MgSO.sub.4), filtered,
concentrated and chromatographed on silica gel with 10-30% ethyl
acetate in hexanes as the eluent to give the title compound.
Example 391B
5-ethynyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
EXAMPLE 391A (0.205 g) in tetrahydrofuran (3 ml) at ambient
temperature was treated with tetrabutyl ammonium fluoride (1 M in
tetrahydrofuran) (0.906 ml) and stirred at ambient temperature for
4 hours. Additional tetrabutyl ammonium fluoride (1 M in
tetrahydrofuran) (1.8 mL) was added and the mixture was heated at
40.degree. C. for 45 minutes. Solid tetrabutyl ammonium fluoride
(0.253 g) was added and heating was continued for 30 minutes. The
reaction mixture was concentrated and then chromatographed on
silica gel using 0-2% methanol in dichloromethane as the eluent to
give the title compound.
Example 391C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfon-
yl}-2-(1H-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
26C and EXAMPLE 391B for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 11.23 (s, 1H),
8.50 (d, 1H), 8.09 (d, 1H), 7.56 (d, 1H), 7.34 (m, 2H), 7.28 (m,
1H), 7.18 (d, 1H), 7.04 (m, 2H), 6.98 (t, 1H), 6.70 (dd, 1H), 6.44
(d, 1H), 6.27 (m, 2H), 4.55 (s, 1H), 4.25 (d, 2H), 3.87 (dd, 2H),
3.34 (m, 2H), 3.06 (m, 4H), 2.81 (m, 1H), 2.20 (m, 6H), 2.04 (m,
1H), 1.96 (m, 2H), 1.65 (dd, 2H), 1.35 (m, 5H), 0.92 (m, 6H).
Example 392
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-i-
ndol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
26C and EXAMPLE 388B for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.15 (s, 1H), 10.99
(s, 1H), 8.64 (d, 1H), 8.33 (d, 1H), 7.58 (d, 1H), 7.35 (d, 2H),
7.24 (m, 1H), 7.07 (m, 3H), 6.89 (m, 1H), 6.66 (dd, 1H), 6.26 (m,
3H), 4.59 (t, 2H), 3.58 (m, 4H), 3.05 (m, 4H), 2.87 (m, 4H), 2.62
(m, 4H), 2.24 (m, 6H), 1.98 (m, 2H), 1.40 (t, 2H), 0.93 (s,
6H).
Example 393
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-y-
l}sulfonyl)-2-(1H-indol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 55B for EXAMPLE
26C and EXAMPLE 385B for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.17 (s, 1H), 8.66
(s, 1H), 8.36 (s, 1H), 7.58 (d, 1H), 7.36 (d, 2H), 7.25 (s, 1H),
7.07 (m, 3H), 6.89 (m, 1H), 6.68 (m, 1H), 6.27 (m, 3H), 4.60 (s,
1H), 4.54 (s, 1H), 3.78 (m, 2H), 3.60 (m, 2H), 3.33 (m, 2H), 3.09
(m, 4H), 2.92 (m, 2H), 2.36 (m, 2H), 2.16 (m, 2H), 1.97 (s, 2H),
1.87 (m, 4H), 1.40 (t, 2H), 0.93 (s, 6H).
Example 394
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(3-hydroxy-4-methoxyphenyl)amino]-3-nitrophenyl}sulfonyl)-2-(-
1H-indol-5-yloxy)benzamide
This example was prepared by substituting 5-amino-2-methoxyphenol
for 1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.
Example 395
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(2,3-dihydro-1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 103 (676 mg) and NaCNBH.sub.3 (49 mg) were combined in
acetic acid (10 mL) and stirred at room temperature overnight. The
reaction was diluted with water and extracted with 95/5
CH.sub.2Cl.sub.2/methanol. The organic layer was concentrated and
the crude material was purified by preparative HPLC using a C18
column, 250.times.50 mm, 10.mu., and eluting with a gradient of
20-100% CH.sub.3CN vs. 0.1% trifluoroacetic acid in water, giving
the title compound as a bistrifluoroacetate salt. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.57 (br s, 1H), 9.70,
9.50 (both v br s, total 2H), 8.57 (d, 1H), 8.20 (br d, 1H), 7.85
(dd, 1H), 7.50 (d, 1H), 7.40 (d, 2H), 7.26 (d, 1H), 7.10 (d, 2H),
6.82 (dd, 1H), 6.75 (dd, 1H), 6.40 (d, 1H), 6.27 (d, 1H), 5.94 (d,
1H), 4.00, 3.70 (both v br m, total 8H),3.55 (v br m, 3H), 3.42 (t,
2H), 3.37 (v br m, 1H), 3.10 (br m, 2H), 2.80 (m, 6H), 2.20 (br m,
4H), 2.03 (s, 2H), 1.82 (br m, 2H), 1.46 (t, 2H), 0.96 (s, 6H).
Example 396
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(pyr-
idin-3-ylamino)benzamide
Example 396A
Methyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)pipera-
zin-1-yl)-2-(pyridin-3-ylamino)benzoate
A solution of EXAMPLE 18E (500 mg), cesium carbonate (429 mg),
palladium (11) acetate (21 mg),
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (58.5 mg) and
toluene (6.4 mL) was degassed with N.sub.2. The mixture was stirred
at 115.degree. C. for 5 minutes. After cooling to room temperature,
pyridin-3-amine (106 mg) was added and the reaction mixture was
degassed again with N.sub.2 and was stirred at 115.degree. C. for
45 minutes. The mixture was cooled to room temperature, diluted
with ethyl acetate and was washed with H.sub.2O, brine, dried
(MgSO.sub.4), filtered and concentrated. The crude product was
purified by flash chromatography on silica gel, eluting with
CH.sub.2Cl.sub.2/1% methanol to afford the title compound.
Example 396B
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(pyridin-3-ylamino)benzoic acid, 2 Hydrochloric Acid
This example was prepared by substituting EXAMPLE 396A for EXAMPLE
224C in EXAMPLE 224D.
Example 396C
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-N-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonyl)-2-(pyridin-3--
ylamino)benzamide
This example was prepared by substituting EXAMPLE 396B for EXAMPLE
26C and EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.32-11.40 (br s, 1H),
9.21-9.39 (br s, 1H), 8.51 (d, 1H), 8.33 (d, 1H), 8.09 (dd, 1H),
7.98-8.07 (m, 1H), 7.94 (dd, 1H), 7.81 (d, 1H), 7.52-7.58 (m, 1H),
7.36 (d, 2H), 7.24-7.30 (m, 1H), 7.15 (d, 1H), 7.08 (d, 2H), 6.53
(d, 1H), 6.33 (dd, 1H), 3.81-3.96 (br s, 2H), 3.02-3.12 (br s, 6H),
2.67-2.80 (m, 5H), 2.07-2.32 (m, 8H), 1.98 (s, 3H), 1.70-1.85 (br
s, 1H), 1.41 (t, 3H), 0.95 (s, 6H).
Example 397
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pheny-
l}sulfonyl)-2-(pyridin-3-ylamino)benzamide
This example was prepared by substituting EXAMPLE 396B for EXAMPLE
26C and EXAMPLE 173C for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 9.10-9.33 (br s, 1H),
8.53 (d, 1H), 8.36 (d, 1H), 8.12 (dd, 1H), 8.00-8.07 (m, 1H), 7.96
(dd, 1H), 7.80 (d, 1H), 7.53-7.59 (m, 1H), 7.38 (d, 2H), 7.25-7.31
(m, 1H), 7.20 (d, 1H), 7.09 (d, 2H), 6.53 (s, 1H), 6.36 (m, 1H),
4.28-4.75 (br s, 1H), 3.90-4.09 (m, 8H), 3.51-3.61 (m, 2H), 3.35
(m, 8H), 3.01-3.18 (br s, 4H), 2.15-2.26 (m, 1H), 1.88-2.09 (m,
5H), 1.56-1.86 (m, 4H), 1.44 (t, 2H), 0.96 (s, 6H).
Example 398
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pheny-
l}sulfonyl)-2-(pyridin-3-yloxy)benzamide
Example 398A
4-Fluoro-2-(pyridin-3-yloxy)-benzoic acid methyl ester
This example was prepared by substituting methyl
2,4-difluorobenzoate for ethyl 2,4-difluorobenzote and
3-hydroxypyridine for 5-hydroxyindazole in EXAMPLE 20A.
Example 398B
4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1--
yl}-2-(pyridin-3-yloxy)-benzoic acid methyl ester
This example was prepared by substituting EXAMPLE 398A for EXAMPLE
20A in EXAMPLE 20D.
Example 398C
4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1--
yl}-2-(pyridin-3-yloxy)-benzoic acid
This example was prepared by substituting EXAMPLE 398B for EXAMPLE
1D in EXAMPLE 1E.
Example 398D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(pyridin-3-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperi-
din-4-yl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 398C for EXAMPLE
1E and EXAMPLE 173C for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 8.36 (d, 1H), 8.11 (t, 1H),
8.08 (t, 2H), 7.70 (dd, 1H), 7.60 (d, 1H), 7.37 (d, 2H), 7.15
(dd,), 7.10-7.03 (m 3H), 7 (dd, H), 6.73 (d, 6.43 (d, 1H),
3.99-3.93 (m, 3H), 3.86 (m, 1H), 3.13 (m, 6H), 2.78 (br s, 2H),
2.30-2.05 (m, 10H), 1.98 (br s, 2H), 1.92-1.67 (m, 6H), 1.57 (m,
2H), 1.41 (t, 2H), 0.94 (s, 6H).
Example 399
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-(1,2,3,4-tetrahydroisoquinolin-5-yloxy)benzamide
Example 399A
tert-butyl 5-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate
A mixture of 1,2,3,4-tetrahydroisoquinolin-5-ol hydrochloric acid
(1.0 g), di-tert-butyl dicarbonate (1.27 g) and 1.0 N NaOH (14.5
mL) in dioxane (20 mL) was stirred at room temperature for 16
hours. The reaction mixture was partitioned between water and ethyl
acetate. The aqueous layer was neutralized with 5% HCl. The
combined organic layers were washed with brine, dried (MgSO.sub.4),
filtered, and concentrated. The residue was purified by flash
chromatography on silica gel to give the title compound.
Example 399B
tert-butyl
5-(2-(ethoxycarbonyl)-5-fluorophenoxy)-3,4-dihydroisoquinoline--
2(1H)-carboxylate
This example was prepared by substituting EXAMPLE 399A for
5-hydroxyindazole in EXAMPLE 20A.
Example 399C
tert-butyl
5-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl-
)piperazin-1-yl)-2-(ethoxycarbonyl)phenoxy)-3,4-dihydroisoquinoline-2(1H)--
carboxylate
This example was prepared by substituting EXAMPLE 399B for EXAMPLE
20A in EXAMPLE 20D.
Example 399D
2-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yloxy)-4-(4-((2-
-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoi-
c acid
This example was prepared by substituting EXAMPLE 399C for EXAMPLE
1D in EXAMPLE 1E.
Example 399E
2-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yloxy)-4-(4-((2-
-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoi-
c 3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonic
anhydride
This example was prepared by substituting EXAMPLE 399D for EXAMPLE
26C in EXAMPLE 177.
Example 399F
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-(1,2,3,4-tetrahydroisoquinolin-5-yloxy)benzamide
A mixture of EXAMPLE 399E (0.058 g) and trifluoroacetic acid (1 mL)
in dichloromethane (10 mL) was stirred for 2 hours. The solvent was
removed, and the residue was taken into ethyl acetate. It was then
washed with saturated NaHCO.sub.3, brine, dried over MgSO.sub.4,
filtered, and concentrated to give the title compound. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.36 (t, 1H), 8.27 (d,
1H), 7.65 (d, 1H), 7.36 (d, 2H), 7.07 (d, 2H) 6.93-6.97 (m, 2H),
6.73 (d 1H), 6.69 (dd, 1H), 6.33 (d, 1H), 6.26 (d, 1H), 4.19 (s,
2H), 3.85 (dd, 2H), 3.05-3.09 (m, 6H), 2.77 (s, 2H), 2.17-2.24 (m,
6H), 1.98-1.99 (m, 2H), 1.60-1.63 (m, 2H0, 1.41 (t, 2H), 0.94 (s,
6H).
Example 400
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indazol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethy-
l)amino]phenyl}sulfonyl)benzamide
Example 400A
4-Hydroxy-indazole-1-carboxylic acid tert-butyl ester and
4-hydroxy-indazole-2-carboxylic acid tert-butyl ester
4-Hydroxyindazole (3.94 g) was added to tetrahydrofuran (250 mL)
and cooled to 0.degree. C. using an ice bath. Sodium hydride (60%
dispersion in mineral oil, 1.23 g) was added, and the mixture was
stirred at 0.degree. C. for five minutes. The mixture was allowed
to warm to room temperature and stirred for an additional 20
minutes. The mixture was again cooled to 0.degree. C. using an ice
bath, and tert-butyldimethylchlorosilane (4.65 g) was added. The
mixture was allowed to warm to room temperature and stirred for 16
hours. Solvent volume was reduced under vacuum, the residue vacuum
filtered over a pad of silica gel and washed with ethyl acetate,
and the solvent was removed under vacuum. To the residue was added
acetonitrile (200 mL), di-tert-butyl dicarbonate (7.06 g), and
4-(dimethylamino)pyridine (0.359 g). The mixture was stirred at
room temperature for three hours, and the solvent was removed under
vacuum. To the residue was added tetrahydrofuran (200 mL) and
tetrabutylammonium fluoride (1M in tetrahydrofuran, 82 mL). The
mixture was stirred at room temperature for four days, the solvent
removed under vacuum, and the residue taken up in ethyl acetate.
The mixture was extracted with saturated aqueous ammonium chloride,
extracted with brine, and dried on anhydrous sodium sulfate. The
mixture was vacuum filtered over silica gel, and the solvent
removed under vacuum to give a mixture of the two products, which
was used in the next step without further purification.
Example 400B
4-Fluoro-2-(1H-indazol-4-yloxy)-benzoic acid methyl ester
EXAMPLE 400A (5.56 g) was added to diglyme (200 mL), and potassium
tert-butoxide (1M in tetrahydrofuran, 30.8 mL) was added. The
mixture was mixed at room temperature for 15 minutes, methyl
2,4-difluorobenzoate was added, and the mixture was heated at
115.degree. C. for 16 hours. The mixture was cooled, the solvent
was removed under vacuum, the residue was taken up in
dichloromethane (100 mL), and trifluoroacetic acid (22.6 mL) was
added. The mixture was stirred at room temperature for 16 hours,
the solvent was removed under vacuum, the residue was taken up in
ethyl acetate and washed with a saturated aqueous sodium
bicarbonate mixture, and the organic layer was dried with anhydrous
sodium sulfate. The material was purified by flash column
chromatography on silica gel using 30% ethyl acetate (in hexanes)
increasing to 40% ethyl acetate (in hexanes).
Example 400C
2-(1H-Indazol-4-yloxy)-4-piperazin-1-yl-benzoic acid methyl
ester
EXAMPLE 400B (2.00 g) and piperazine (2.71 g) were added to
dimethylsulfoxide (60 mL) and heated to 100.degree. C. for one
hour. The mixture was cooled, added to dichloromethane, washed with
water twice, washed with a saturated aqueous sodium bicarbonate
mixture, and dried on anhydrous sodium sulfate. After filtration,
the solvent was removed under vacuum.
Example 400D
4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1--
yl}-2-(1H-indazol-4-yloxy)-benzoic acid methyl ester
This example was prepared by substituting EXAMPLE 218A for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 400C for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 400E
4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1--
yl}-2-(1H-indazol-4-yloxy)-benzoic acid
This example was prepared by substituting EXAMPLE 400D for EXAMPLE
1D in EXAMPLE 1E.
Example 400F
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indazol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethy-
l)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 400E for EXAMPLE
1E in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 13.09 (s, 1H), 8.56 (t, 1H), 8.38 (d, 1H), 7.80 (s, 1H),
7.56 (dd, 1H), 7.53 (d, 1H), 7.36 (d, 2H), 7.16-7.05 (m, 4H), 6.99
(d, 1H), 6.80 (dd, 1H), 6.52 (d, 1H), 6.19 (dd, 1H), 3.87 (dd, 2H),
3.25-3.12 (m, 6H), 2.78 (m, 2H), 2.30-2.16 (m, 6H), 1.97 (br s,
2H), 1.90 (m, 1H), 1.63 (m, 2H), 1.53 (m, 1H), 1.40 (t, 2H), 1.29
(m, 3H), 0.94 (s, 6H).
Example 401
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indazol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpip-
eridin-4-yl)amino]phenyl}sulfonyl)benzamide
Example 401A
N-[(4-chloro-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 400E for EXAMPLE
1E and 4-chloro-3-nitrobenzenesulfonamide for EXAMPLE 1F in EXAMPLE
1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 13.04
(s, 1H), 8.17 (br s, 1H), 7.75 (s, 1H), 7.73 (d, 1H), 7.66-7.61 (m,
2H), 7.38 (d, 2H), 7.11-7.01 (m, 4H), 6.79 (dd, 1H), 6.54 (d, 1H),
6.10 (dd, 1H), 3.38-3.05 (m, 8H), 2.73 (br s, 2H), 2.19 (m, 2H),
2.00 (br s, 2H), 1.44 (t, 2H), 0.95 (s, 6H).
Example 401B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indazol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpip-
eridin-4-yl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 173B for
1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 401A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 13.05 (br s, 1H), 8.35
(d, 1H), 8.13 (d, 1H), 7.78 (s, 1H), 7.61-7.52 (m, 2H), 7.35 (d,
2H), 7.11-7.03 (m, 4H), 6.98 (d, 1H), 6.77 (dd, 1H), 6.48 (d, 1H),
6.18 (m, 1H), 3.69-3.52 (m, 4H), 3.12 (m, 6H), 2.76 (br s, 2H),
2.67 (m, 4H), 2.28-2.16 (m, 6H), 2.09-2.01 (m, 2H), 1.97 (br s,
2H), 1.95 (m, 2H), 1.50-1.38 (m, 6H), 0.93 (s, 6H).
Example 402
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-indazol-4-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide
This example was prepared by substituting
trans-4-morpholin-4-yl-cyclohexylamine for
1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 401A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A. .sup.1H NMR
(300 MHz, dimethylsulfoxide-d.sub.6) .delta. 13.02 (br s, 1H), 8.35
(d, 1H), 8.12 (m, 1H), 7.75 (s, 1H), 7.65-7.55 (m, 2H), 7.35 (d,
2H), 7.10-7.03 (m, 4H), 6.97 (m, 1H), 6.76 (dd, 1H), 0.4 (m, 1H),
6.17 (t, 1H), 3.95 (m, 2H), 3.77 (m, 1H), 3.62 (m, 1H), 3.10 (m,
6H), 2.75 (br s, 2H), 2.28-2.14 (m, 8H), 2.06 (m, 2H), 1.97 (br s,
2H), 1.85 (m, 2H), 1.71 (m, 2H), 1.55 (m, 4H), 1.40 (t, 2H), 0.93
(s, 6H).
Example 403
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-yl-
methyl)amino]phenyl}sulfonyl)benzamide
Example 403A
methy 4-fluoro-2-(3-fluoro-2-nitrophenoxy)benzoate
To a solution of methyl 4-fluoro-2-hydroxybenzoate (3.0 g) in
tetrahydrofuran (65 mL) was added potassium t-butoxide (1.979 g)
portion wise. The resulting solution was stirred at ambient
temperature for 30 minutes and a solution of
1,3-difluoro-2-nitrobenzene (2.338 g) in tetrahydrofuran (15 mL)
was added dropwise. After 1 hour, the reaction was heated at reflux
for 18 hours. The reaction was quenched with water (10 mL), diluted
with brine (75 mL) and extracted with methylene chloride
(2.times.75 mL). The crude product was isolated by concentration
and purified on silica gel, eluted with a 10, 20, 50% ethyl acetate
in hexane step gradient to provide the title compound.
Example 403B
methyl
2(3-(bis(4-methoxyphenyl)methylamino)-2-nitrophenoxy)-4-fluorobenzo-
ate
To a solution of EXAMPLE 403A (3.82 g) and
bis(4-methoxyphenyl)methanamine (4.51 g) in
N-methyl-2-pyrrolidinone (65 mL) was added
N-ethyl-N-isopropylpropan-2-amine (4.30 mL) and the mixture was
heated at 100.degree. C. for 24 hours. The crude product, isolated
by concentration, was purified on silica gel, and was eluted with a
10, 25, and 65% ethyl acetate in hexane step gradient to provide
the title compound.
Example 403C
methyl
2-(2-amino-3-(bis(4-methoxyphenyl)methylamino)phenoxy)-4-fluorobenz-
oate
To a solution of EXAMPLE 403B (2.76 g) in tetrahydrofuran (125 mL)
in a stainless steel pressure bottle was added nickel catalyst
(2.76 g). The mixture was stirred for 1 hour under hydrogen at 30
psi and ambient temperature. The mixture was filtered though a
nylon membrane to remove the catalyst, and concentrated to give the
product.
Example 403D
methyl
2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-fl-
uorobenzoate
To a solution EXAMPLE 403C (1.25 g) in triethyl orthoformate (30
mL) was added concentrated hydrochloric acid (0.75 mL). The mixture
was stirred for 18 hours, quenched by the slow addition of 50%
saturated aqueous sodium carbonate solution (100 mL) and extracted
with ethyl acetate (2.times.100 mL). The crude product was isolated
by concentration and purified on silica gel, and was eluted with a
25, 50, and 70% ethyl acetate in hexane step gradient to provide
title compound.
Example 403E
methyl
2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(p-
iperazin-1-yl)benzoate
A solution of EXAMPLE 403D (500 mg), and piperazine (420 mg) in
dimethylsulfoxide (9 mL) was heated at 100.degree. C. for 3 hours.
The crude product was isolated by concentration and, following an
aqueous work up, it was purified on silica gel, and was eluted with
a 5 and 10% methanol in methylene chloride step gradient to provide
the title compound.
Example 403F
methyl
2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(4-
-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)be-
nzoate
To a solution of EXAMPLE 403E (430 mg) and EXAMPLE 218A (259 mg) in
dichloromethane (13 mL) was added sodium triacetoxyborohydride (323
mg) portionwise. After stirring 42 hours, the reaction was quenched
slowly with saturated aqueous sodium bicarbonate solution (80 mL)
and extracted with methylene chloride (2.times.70 mL). The crude
product was isolated by concentration and purified on silica gel,
and was eluted with a 0, 2, 10% methanol in methylene chloride step
gradient to provide the title compound.
Example 403G
2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-
-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic
acid
To a solution of EXAMPLE 403F (545 mg) in a mixture of methanol
(7.50 mL) and tetrahydrofuran (7.50 mL) was added a solution of
sodium hydroxide (269 mg) in water (3.0 mL). The reaction mixture
was heated at 50.degree. C. for 18 hours and then concentrated. The
residue was mixed with water (100 mL) and the pH was adjusted to
ca. 7 with 1M aqueous hydrochloric acid. The mixture was extracted
with 10% methanol in methylene chloride (10.times.50 mL), and the
combined organic layers were concentrated to provide the title
compound.
Example 403H
2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-
-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nit-
ro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide
To a solution of EXAMPLE 403G (200 mg), EXAMPLE 1F (99 mg),
triethylamine (0.122 mL), N,N-dimethylpyridin-4-amine (77 mg) in a
mixture of dichloromethane (8 mL) and N, N-dimethylformamide (1 mL)
was added
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloric acid (96 mg). The reaction mixture was stirred 18
hours and then concentrated. The crude product was purified on
silica gel eluted with an 80 and 100% ethyl acetate in hexane step
gradient to provide the title compound.
Example 403I
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-yl-
methyl)amino]phenyl}sulfonyl)benzamide
A solution of EXAMPLE 403H (174 mg) and dichloromethane (25 mL) was
cooled in an ice bath and 2,2,2-trifluoroacetic acid (25 mL) was
added slowly dropwise. The reaction mixture was stirred 30 minutes
under nitrogen and the ice bath was removed. The reaction was
stirred 18 hours and then concentrated. The crude product was
purified by reverse phase chromatography with ammonium acetate
buffer in acetonitrile to give the title compound. .sup.1H NMR (400
MHz, pyridine-d.sub.5) .delta. 9.30 (d, 1H), 8.69 (t, 1H), 8.59 (s,
1H), 8.42 (dd, 1H), 7.99 (d, 1H), 7.53 (d, 1H), 7.43 (d, 2H), 7.26
(m, 1H), 7.18 (m, 1H), 7.06 (d, 2H), 6.94 (d, 1H), 6.72-6.66 (m,
2H), 5.53 (m, 2H), 3.98 (m, 2H), 3.32 (m, 2H), 3.18 (t, 2H), 2.03
(m, 4H), 2.76 (s, 2H), 2.25 (m, 2H), 2.13 (m, 4H), 1.97 (s, 2H),
1.83 (m, 1H), 1.60 (m, 2H), 1.40-1.29 (m, 4H), 0.94 (s, 6H).
Example 404
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sul-
fonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide
Example 404A
5-chloro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonami-
de
The title compound was prepared by substituting EXAMPLE 387A for
EXAMPLE 329A and EXAMPLE 306C for
(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 329B.
Example 404B
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sul-
fonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 404A for
EXAMPLE 1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 13.09 (s, 1H),
8.27 (d, 1H), 7.88 (d, 1H), 7.80 (s, 1H), 7.60 (d, 1H), 7.37 (d,
2H), 7.03-7.10 (m, 4H), 6.79 (dd, 1H), 6.53 (d, 1H), 6.13 (d, 1H),
4.50 (d, 2H), 3.76-3.81 (m, 2H), 3.57-3.63 (m, 2H), 3.04 (br s,
4H), 2.84 (br s, 2H), 2.18 (m, 2H), 1.82-1.92 (m, 4H), 1.42 (t,
2H), 0.94 (s, 6H).
Example 405
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sul-
fonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(1H-indol-4-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 404A for
EXAMPLE 1F and EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.21 (s, 1H),
8.43 (d, 1H), 8.06 (d, 1H), 7.55 (d, 1H), 7.34 (d, 2H), 7.27 (t,
1H), 7.13 (d, 1H), 7.04 (d, 2H), 6.93 (t, 1H), 6.69 (dd, 1H), 6.36
(d, 1H), 6.28 (d, 1H), 6.26 (d, 1H), 4.51 (d, 2H), 3.73-3.79 (m,
2H), 3.55-3.61 (m, 2H), 3.08 (br s, 4H), 2.86 (br s, 2H), 2.31 (br
s, 2H), 2.18 (m, 2H), 1.95 (s, 2H), 1.79-1.90 (m, 4H), 1.36 (t,
2H), 0.92 (s, 6H).
Example 406
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-y-
l}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 385B for
EXAMPLE 1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 13.03 (s, 1H),
8.48 (d, 1H), 8.17 (s, 1H), 7.74 (s, 1H), 7.63 (d, 1H), 7.37 (d,
2H), 7.00-7.08 (m, 4H), 6.77 (dd, 1H), 6.51 (s, 1H), 6.07 (d, 1H),
4.55 (d, 2H), 3.77-3.81 (m, 2H), 3.58-3.63 (m, 2H), 3.20 (br s,
4H), 2.19 (br s, 2H), 1.99 (s, 2H), 1.85-1.92 (m, 4H), 1.42 (t,
2H), 0.94 (s, 6H).
Example 407
2-(H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex--
1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrroli-
din-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide
Example 407A
(R)-tert-butyl 1-(2,2-difluoroethyl)pyrrolidin-3-ylcarbamate
To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (500 mg),
1,1-difluoro-2-iodoethane (618 mg) in N,N-dimethylformamide (6 mL)
was added N-ethyl-N-isopropylpropan-2-amine (1.403 mL) and the
reaction stirred for 72 hours at 70.degree. C. The reaction mixture
was concentrated and the crude product was purified on a silica gel
and was eluted with a 0, 2, and 5% methanol in methylene chloride
step gradient to provide the title compound.
Example 407B
(R)-1-(2,2-difluoroethyl)pyrrolidin-3-amine
To a solution of EXAMPLE 407A (525 mg) in a mixture of
dichloromethane (3 mL) and methanol (2.0 mL) was added hydrogen
chloride, 4M in dioxane (5.24 mL). The reaction was stirred for 3
hours, and concentrated to provide the title compound.
Example 407C
(R)-4-(1-(2,2-difluoroethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamid-
e
To a solution of EXAMPLE 407B (468 mg) in tetrahydrofuran (20 mL),
N-ethyl-N-isopropylpropan-2-amine (2.193 mL) and
N,N-dimethylformamide (2 mL) was added
4-fluoro-3-nitrobenzenesulfonamide (473 mg) and the reaction
mixture was stirred 72 hours.
The crude product was isolated by concentration and was purified on
silica gel, and was eluted with a 0.5, 2.5, and 5% methanol in
methylene chloride step gradient to obtain the title compound.
Example 407D
(R)-2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(4-((-
2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-nitrophe-
nylsulfonyl)benzamide
The title compound was prepared by substituting EXAMPLE 407C for
EXAMPLE 1F in EXAMPLE 403H.
Example 407E
2-(1H-benzimidazol-4-yloxy)-4-(4-({[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrro-
lidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide
The title compound was prepared by substituting EXAMPLE 407D for
EXAMPLE 403H in EXAMPLE 4031. .sup.1H NMR (400 MHz,
pyridine-d.sub.5) .delta. 9.26 (d, 1H), 8.60-8.55 (m, 2H), 8.39 (m,
1H), 7.99 (d, 1H), 7.53 (d, 1H), 7.43 (d, 2H), 7.25 (m, 1H), 7.17
(m, 1H), 7.06 (d, 2H), 6.86 (d, 1H), 6.72-6.69 (m, 2H), 6.00-6.33
(m, 1H), 5.27 (m, 2H), 4.09 (m, 1H), 3.03 (m, 4H), 2.96-2.86 (m,
4H), 2.81-2.74 (m, 3H), 2.48 (m, 1H), 2.26 (m, 3H), 2.13 (m, 4H),
1.97 (s, 2H), 1.67 (m, 1H), 1.38 (t, 2H), 0.94 (s, 6H).
Example 408
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl-
)methoxy]-3-nitrophenyl}sulfonyl)benzamide
Example 408A
2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-
-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((4-
-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrophenylsulfonyl)benzamide
The title compound was prepared by substituting EXAMPLE 306D for
EXAMPLE 1F in EXAMPLE 403H.
Example 408B
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl-
)methoxy]-3-nitrophenyl}sulfonyl)benzamide
The title compound was prepared by substituting EXAMPLE 408A for
EXAMPLE 403H in EXAMPLE 4031. .sup.1H NMR (400 MHz,
pyridine-d.sub.5) .delta. 9.01 (d, 1H), 8.57 (m, 2H), 7.99 (d, 1H),
7.53 (d, 1H), 7.44 (d, 2H), 7.25 (m, 1H), 7.21 (m, 1H), 7.12 (d,
1H), 7.07 (d, 2H), 6.73-6.70 (m, 2H), 5.35 (m, 2H), 4.36 (s, 1H),
4.31 (s, 1H), 3.88 (m, 2H), 3.78 (m, 2H), 3.05 (m, 4H), 2.77 (s,
2H), 2.26 (m, 2H), 2.15 (m, 4H), 2.07-192 (m, 6H), 1.39 (t, 2H),
0.94 (s, 6H).
Example 409
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide
Example 409A
(4-fluorotetrahydro-2H-pyran-4-yl)methyl methanesulfonate
A mixture of EXAMPLE 306C (1.4 g), methanesulfonyl chloride (1.054
mL), triethylamine (2.99 mL), and 4-(dimethylamino)pyridine (0.051
g) in CH.sub.2Cl.sub.2 (20 mL) was stirred at 0.degree. C. for 2
hours, concentrated and chromatographed on silica gel with 30%
ethyl acetate in hexanes as eluent to give the product.
Example 409B
2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)isoindoline-1,3-dione
A mixture of EXAMPLE 409A (1.8 g) and potassium phthalimide (2.356
g) in N,N-dimethylformamide (30 mL) was heated at 150.degree. C.
overnight, diluted with ethyl acetate, washed with water and brine,
dried (MgSO.sub.4), filtered, concentrated and chromatographed on
silica gel with 30% ethyl acetate in hexanes as eluent to give the
product.
Example 409C
(4-fluorotetrahydro-2H-pyran-4-yl)methanamine
A mixture of EXAMPLE 409B (1.4 g) and hydrazine (1.548 mL) in
ethanol (40 mL) was heated at 70.degree. C. overnight, cooled to
room temperature, slurried with CH.sub.2C.sub.12 (200 mL) and the
solid removed by filtration. The filtrate was concentrated and
chromatographed on silica gel with 100:5:1 ethyl
acetate/methanol/NH.sub.4OH as eluent to give the product.
Example 409D
4-((4-fluorotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamid-
e
A mixture of 4-fluoro-3-nitrobenzenesulfonamide (0.44 g), EXAMPLE
409C (0.266 g), and triethylamine (1.11 mL) in tetrahydrofuran (10
mL) was heated at 70 OC overnight, diluted with ethyl acetate,
washed with water and brine, dried (MgSO.sub.4), filtered,
concentrated and chromatographed on silica gel with 50% ethyl
acetate in hexanes as eluent to give the product.
Example 409E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitropheny-
l)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 409D for
EXAMPLE 1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 13.09 (s, 1H),
8.59 (t, 1H), 8.37 (d, 1H), 7.80 (s, 1H), 7.59 (dd, 1H), 7.37 (d,
2H), 7.04-7.13 (m, 5H), 6.79 (dd, 1H), 6.51 (d, 1H), 6.18 (d, 1H),
3.70-3.79 (m, 4H), 3.50-3.56 (m, 2H), 3.15 (br s, 4H), 2.78 (br s,
2H), 2.32 (br s, 4H), 2.17 (br s, 2H), 1.97 (s, 2H), 1.75-1.83 (m,
4H), 1.40 (t, 2H), 0.93 (s, 6H).
Example 410
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethyl-
)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide
Example 410A
5-nitro-3-(trifluoromethyl)pyridin-2-ol
3-(Trifluoromethyl)pyridin-2-ol (2.3 g) was added to concentrated
sulfuric acid (15 mL) at 0.degree. C. The mixture was stirred at
0.degree. C. for 5 minutes. To this solution was added nitric acid
(fuming) (6 mL) dropwise over 5 minutes. The reaction mixture was
stirred at room temperature for 2 hours, and was heated at
50.degree. C. for 3 hours. After cooling, the reaction mixture was
poured into ice (200 g), and the mixture was extracted with ethyl
acetate three times. The combined organic layers were washed with
brine, dried over MgSO.sub.4, filtered, and concentrated under
reduced pressure to give the title compound.
Example 410B
2-chloro-5-nitro-3-(trifluoromethyl)pyridine
A mixture of EXAMPLE 410A (1.69 g), phosphorus pentachloride (2.03
g), and phosphoryl trichloride (0.97 mL) was heated at 90.degree.
C. for 3 hours. After cooling, the reaction mixture was poured into
ice, and extracted with ethyl acetate three times. The extract was
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel eluting with 1:9 ethyl
acetate\hexanes to give the title compound.
Example 410C
A mixture of iron (1.5 g) and ammonium chloride (2.38 g) in water
(40 mL) was stirred at room temperature for 5 minutes. To this
suspension was added EXAMPLE 410B in methanol (40 mL). The reaction
mixture was stirred at room temperature for 1 hour. Additional iron
(1.8 g) was added to the reaction mixture, and it was stirred for
another 3 hours. The solid from the reaction mixture was filtered
off, and the filtrate was partitioned between water and ethyl
acetate. The combined organic layers were washed with brine, dried
over MgSO.sub.4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica
gel eluting with 1:4 ethyl acetate\hexanes to give the title
compound.
Example 410D
6-chloro-5-(trifluoromethyl)pyridine-3-sulfonyl chloride
Under ice-cooling, thionyl chloride (4 mL) was added dropwise over
20 minutes to water (27 mL). The mixture was stirred overnight for
12 hours to give a SO.sub.2 containing solution. Separately,
EXAMPLE 410C (1.14 g) in dioxane (5 mL) was added to concentrated
HCl (20 mL) at 0.degree. C. The solution was stirred for 5 minutes.
To this mixture was added sodium nitrite (0.44 g) in water (6 mL)
dropwise at 0.degree. C. The solution stirred at 0.degree. C. for
three hours. During this time, any solids formed were crushed with
a glass rod to make sure that EXAMPLE 410C was completely reacted.
To the SO.sub.2 containing solution was added copper(I) chloride
(0.115 g). Then, to this solution was added the diazotized EXAMPLE
410C at 0.degree. C. The solution was stirred for 30 minutes. The
reaction mixture was extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over MgSO.sub.4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel eluting with
1:20 ethyl acetate\hexanes to give the title compound.
Example 410E
6-chloro-5-(trifluoromethyl)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 410D for
5-bromo-6-chloropyridine-3-sulfonyl chloride in EXAMPLE 329A.
Example 410F
The title compound was prepared by substituting EXAMPLE 410E for
EXAMPLE 329A and EXAMPLE 306C for
(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 329B.
Example 410G
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethyl-
)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 410F for
EXAMPLE 1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177. .sup.1H
NMR (500 MHz dimethylsulfoxide-d.sub.6) 13.05 (s 1H), 8.59 (s, 1H),
8.17 (d, 1H) 776 (s, 1H), 7.62 (d, 1H), 7.37 (d, 2H), 7.00-7.08 (m,
4H), 6.78 (dd, 1H), 6.51 (s, 1H), 6.11 (d, 1H), 4.56 (d, 2H),
3.77-3.80 (m, 2H), 3.57-3.62 (m, 2H), 3.18 (br s, 2H), 2.32 (br s,
4H), 2.18 (br s, 2H), 1.99 (s, 2H), 1.81-1.90 (m, 4H), 1.42 (t,
2H), 0.94 (s, 6H).
Example 411
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sul-
fonyl]-2-(1H-indazol-4-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 400E for
EXAMPLE 1E and EXAMPLE 432A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 13.09 (s, 1H),
8.57 (m, 1H), 8.37 (d, 1H), 7.81 (s, 1H), 7.56 (dd, 1H), 7.52 (d,
1H), 7.38-7.31 (m, 3H), 7.11-7.07 (m, 3H), 6.97 (d, 1H), 6.80 (dd,
1H), 6.52 (d, 1H), 6.17 (d, 1H), 3.84 (d, 1H), 3.24-3.10 (m, 6H),
2.93 (d, 2H), 2.76 (m, 2H), 2.73 (s, 2H), 2.34-2.10 (m, 8H), 1.97
(bs, 2H), 1.67 (m, 1H), 1.40 (t, 2H), 0.93 (s, 6H), 0.47-0.26 (m,
4H).
Example 412
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl-
]-2-(1H-indazol-4-yloxy)benzamide
Example 412A
tert-butyl(4,4-difluorocyclohexyl)methylcarbamate
Tert-butyl(4-oxocyclohexyl)methylcarbamate (5 g) and
diethylaminosulfur trifluoride (7.45 g) were stirred in
dichloromethane (100 mL) for 24 hours. The mixture was quenched
with pH 7 buffer (100 mL), and poured into ether (400 mL). The
resulting solution was separated, and the organic layer was washed
twice with water, and once with brine, and then concentrated to
give the crude product and fluoroolefin in a 3:2 ratio. The crude
product was taken up in tetrahydrofuran (70 mL) and water (30 mL),
and N-methylmorpholine-N-oxide (1.75 g), and OsO.sub.4 (2.5 wt %
solution in t-butanol) were added, and the mixture was stirred for
24 hours. Na.sub.2S.sub.2O.sub.3 (10 g) was then added, and the
mixture was stirred for 30 minutes. The mixture was then diluted
with ether (300 mL), and the resulting solution was separated, and
rinsed twice with water, and once with brine, and concentrated. The
crude product was chromatographed on silica gel using 5-10% ethyl
acetate in hexanes to give the title compound.
Example 412B
(4,4-difluorocyclohexyl)methanamine
A solution of EXAMPLE 412A (3 g) in dichloromethane (35 mL),
trifluroacetic acid (15 mL), and triethylsilane (1 mL) was stirred
for 2 hours. The solution was concentrated, then concentrated from
toluene, and left on high vacuum for 24 hours. The semi-solid was
taken up in ether/hexane and filtered to give the product as its
trifluroacetic acid salt.
Example 412C
4-((4,4-difluorocyclohexyl)methylamino)-3-nitrobenzenesulfonamide
The title compound was prepared by substituting EXAMPLE 412B for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A.
Example 412D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl-
]-2-(1H-indazol-4-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 400E for
EXAMPLE 1E and EXAMPLE 412C for EXAMPLE 1F in EXAMPLE 1G. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 13.16 (s, 1H),
11.70 (br s, 1H), 8.65 (m, 1H), 8.44 (d, 1H), 7.87 (d, 1H), 7.61
(dd, 2H), 7.41 (d, 2H), 7.02-7.20 (m, 4H), 6.88 (dd, 1H), 6.58 (d,
1H), 6.26 (dd, 1H), 3.22 (m, 4H), 2.86 (m, 2H), 2.20-2.35 (m, 7H),
2.14 (s, 2H), 2.10 (m, 2H), 2.03 (m, 2H), 1.91 (m, 2H), 1.87 (m,
2H), 1.46 (m, 2H), 1.27-1.39 (m, 3H), 1.00 (s, 6H).
Example 413
N-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3--
yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide
Example 413A
The title compound was prepared by substituting EXAMPLE 387A for
4-fluoro-3-nitrobenzenesulfonamide and EXAMPLE 409C for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 413B
N-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3--
yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 413A for
EXAMPLE 1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 13.14 (s, 1H),
8.19 (d, 1H), 7.87 (s, 1H), 7.60 (d, 1H), 7.56 (d, 1H), 7.36 (d,
2H), 7.31 (br s, 1H), 7.08-7.17 (m, 2H), 7.06 (d, 2H), 6.80 (dd,
1H), 6.53 (d, 1H), 6.20 (d, 1H), 3.70-3.78 (m, 4H), 3.43-3.54 (m,
2H), 3.18 (br s, 4H), 2.81 (s, 2H), 2.26 (br s, 4H), 2.17 (br s,
2H), 1.97 (s, 2H), 1.64-1.80 (m, 4H), 1.40 (t, 2H), 0.94 (s,
6H).
Example 414
Trans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indazol-4-yloxy)benzamide
Example 414A
Cis-(4-methoxycyclohexyl)methanol and
Trans-(4-methoxycyclohexyl)methanol
Ethyl 4-methoxycyclohexanecarboxylate (1 g) in tetrahydrofuran (10
mL) was treated with 1.0 N LiAlH.sub.4 in THF (2 mL) at 0.degree.
C. The mixture was stirred for 2 hours. The reaction was quenched
with water (0.6 mL) followed by 2.0 N aqueous NaOH (0.2 mL). The
mixture was stirred for another 20 minutes, and the solid was
filtered off. The filtrate was taken up in ethyl acetate, washed
with brine, dried over MgSO.sub.4, filtered, and concentrated to
give the title compound as a mixture of cis and trans isomers.
Example 414B
5-chloro-6-((trans-4-methoxycyclohexyl)methoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 387A for
EXAMPLE 329A and EXAMPLE 414A for
(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 329B.
The trans isomer was isolated by flash column chromatography on
silica gel.
Example 414C
Trans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indazol-4-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 414B for
EXAMPLE 1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 13.10 (s, 1H),
8.27 (d, 1H), 7.85 (d, 1H), 7.80 (s, 1H), 7.59 (d, 1H), 7.36 (d,
2H), 7.03-7.10 (m, 4H), 6.79 (dd, 1H), 6.53 (d, 1H), 6.14 (d, 1H),
4.19 (d, 2H), 3.24 (s, 3H), 3.20 (m, 4H), 3.07-3.10 (m, 2H), 2.93
(br s, 2H), 2.39 (s, 4H), 2.18 (s, 2H), 1.98-2.02 (m, 4H),
1.70-1.86 (m, 3H), 1.42 (t, 2H), 1.08-1.17 (m, 4H), 0.94 (s,
6H).
Example 415
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin--
2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide
Example 415A
tert-Butyl
2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxyl-
ate
This EXAMPLE was prepared by substituting tert-butyl
2-(aminomethyl)morpholine-4-carboxylate for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 415B
4-(morpholin-2-ylmethylamino)-3-nitrobenzenesulfonamide
A solution of EXAMPLE 415A (0.8 g) in methylene chloride (10 mL)
and trifluoroacetic acid (10 mL) was stirred at room temperature
for 2 hours. The solvents were evaporated and the residue was
triturated with diethyl ether. The resulting solid was dissolved in
5% aqueous sodium carbonate solution (20 mL). The solution was
evaporated to dryness and the resulting solid was triturated with a
solution of 10% methanol in dichloromethane several times.
Evaporation of the organic solution gave the title compound.
Example 415C
4-((4-(2,2-difluoroethyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfona-
mide
To a solution of EXAMPLE 415B (633 mg) in anhydrous
N,N-dimethylformamide (10 mL) was added sodium carbonate (254 mg)
and 2, 2-difluoroethyl iodide (422 mg). After stirring at
110.degree. C. for 48 hours, the mixture was concentrated. The
residue was mixed with water (20 mL) and extracted with ethyl
acetate. The crude product was purified on a silica gel column
eluting with 10% methanol in methylene chloride to give the title
compound.
Example 415D
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin--
2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide
This EXAMPLE was prepared by substituting EXAMPLE 415C for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.26 (d, 1H), 8.87 (t, 1H), 8.57 (s, 1H), 8.37 (dd, 1H),
7.99 (d, 1H), 7.53 (d, 1H), 7.43 (d, 2H), 7.25 (m, 2H), 7.17 (d,
1H), 7.06 (d, 2H), 6.96 (d, 1H), 6.72-6.69 (m, 2H), 6.31, 6.20,
6.09 (tt, 1H), 3.90 (m, 1H), 3.86 (d, 1H), 3.68 (dt, 1H), 3.54-3.41
(m, 2H), 3.03 (m, 4H), 2.97 (d, 1H), 2.83-2.75 (m, 4H), 2.69 (d,
1H), 2.35 (dt, 1H), 2.27-2.23 (m, 3H), 2.14 (m, 4H), 1.97 (s, 2H),
1.38 (t, 2H), 0.94 (s, 6H).
Example 416
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3--
yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide
Example 416A
5-bromo-3-fluoro-2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine
The title compound was prepared by substituting EXAMPLE 306C for
(tetrahydro-2H-pyran-4-yl)methanol and 5-bromo-2,3-difluoropyridine
for 4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 279A.
Example 416B
tert-butyl
5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-
-ylcarbamate
EXAMPLE 416A (0.658 g), tert-butyl carbamate (0.300 g),
palladium(II) acetate (0.024 g),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.093 g) and
cesium carbonate (1.044 g) were combined in a 20-mL vial with
dioxane (10.7 ml). The vial was flushed with nitrogen, capped and
stirred at 100.degree. C. overnight. The reaction mixture was
diluted with ethyl acetate, washed with water and brine, dried
(MgSO.sub.4), filtered, concentrated and chromatographed on silica
gel with 20% ethyl acetate in hexanes as eluent.
Example 416C
5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonyl
chloride
Under ice-cooling, thionyl chloride (1.563 mL) was added dropwise
over 20 minutes to water (9 mL). The mixture was stirred for 12
hours to give a SO.sub.2-containing solution. Separately, EXAMPLE
416B (0.295 g) was added to a mixture of dioxane (3.2 mL) and
concentrated HCl (8 ml) at 0 OC. The solution was stirred for 15
minutes, treated with a solution of sodium nitrite (0.065 g) in
water (2 mL) dropwise at 0.degree. C. and stirred at 0.degree. C.
for three hours. The SO.sub.2-containing solution was cooled to
0.degree. C., treated sequentially with copper(I) chloride (0.042
g) and the diazotized mixture, and stirred for 30 minutes. The
reaction mixture was then extracted with ethyl acetate and the
organic layer was dried (MgSO.sub.4), filtered and concentrated.
The concentrate was chromatographed on silica gel with 5-10% ethyl
acetate in hexanes as eluent.
Example 416D
5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonami-
de
EXAMPLE 416C (0.08 g,) in isopropanol (2 mL) at 0.degree. C. was
treated with ammonium hydroxide (1.70 mL) and stirred overnight.
The reaction mixture was concentrated to dryness, slurried in
water, filtered, rinsed with water and dried under vacuum to
provide the title compound.
Example 416E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3--
yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 400E for
EXAMPLE 26C and EXAMPLE 416D for EXAMPLE 1F in EXAMPLE 177. .sup.1H
NMR (400 MHz, PYRIDINE-d.sub.5) .delta. 14.67 (s, 1H), 8.84 (d,
1H), 8.38 (d, 1H), 8.06 (d, 1H), 8.00 (dd, 1H), 7.46 (m, 2H), 7.35
(d, 1H), 7.12 (m, 3H), 6.87 (m, 2H), 6.47 (d, 1H), 4.56 (d, 2H),
3.80 (m, 4H), 3.18 (m, 4H), 2.83 (s, 2H), 2.31 (t, 2H), 2.24 (m,
4H), 1.99 (s, 2H), 1.86 (m, 4H), 1.41 (t, 2H), 0.96 (s, 6H).
Example 417
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4--
ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide
Example 417A
2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-
-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nit-
ro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)phenylsulfonyl)benza-
mide
The title compound was prepared by substituting EXAMPLE 173C for
EXAMPLE 1F in EXAMPLE 403H.
Example 417B
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4--
ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide
The title compound was prepared by substituting EXAMPLE 417A for
EXAMPLE 403H in EXAMPLE 4031. .sup.1H NMR (500 MHz,
pyridine-d.sub.5) .delta. 9.27 (m, 1H), 8.59 (s, 1H), 8.47 (d, 1H),
8.43 (d, 1H), 8.01 (d, 1H), 7.53 (d, 1H), 7.43 (d, 2H), 7.24 (m,
1H), 7.18 (m, 1H), 7.07 (d, 2H), 6.96 (d, 1H), 6.70 (m, 2H), 5.34
(m, 2H), 4.03 (m, 2H), 3.53 (m, 1H), 3.31 (m, 2H), 3.03 (m, 4H),
2.82 (m, 2H), 2.76 (s, 2H), 2.42 (m, 1H), 2.32 (m, 2H), 2.26-2.19
(m, 2H), 2.14 (m, 4H), 1.98 (m, 4H), 1.67-1.52 (m, 6H), 1.38 (m,
2H), 0.94 (s, 6H).
Example 418
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide
Example 418A
2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-
-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(1--
methylpiperidin-4-ylamino)-3-nitrophenylsulfonyl)benzamide
The title compound was prepared by substituting EXAMPLE 21A for
EXAMPLE 1F in EXAMPLE 403H.
Example 418B
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide
The title compound was prepared by substituting EXAMPLE 418A for
EXAMPLE 403H in EXAMPLE 4031. .sup.1H NMR (500 MHz,
pyridine-d.sub.5) .delta. 9.25 (m, 1H), 8.58 (s, 1H), 8.42 (m, 2H),
8.02 (d, 1H), 7.52 (d, 1H), 7.43 (d, 2H), 7.23 (m, 1H), 7.14 (d,
1H), 7.07 (d, 2H), 6.92 (d, 1H), 6.70 (m, 2H), 5.52 (m, 2H), 3.50
(m, 1H), 3.03 (m, 4H), 2.77 (s, 2H), 2.68 (m, 2H), 2.25 (m, 2H),
2.20 (s, 3H), 2.14 (m, 6H), 1.97-1.90 (m, 4H), 1.67 (m, 2H), 1.38
(t, 2H), 0.94 (s, 6H).
Example 419
N-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3--
yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(l 1H-indazol-4-yloxy)benzamide
Example 419A
tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate
1-Tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (1.0 g)
in tetrahydrofuran (10 mL) at 0.degree. C. was treated with a 1 N
solution of LiAlH.sub.4 in tetrahydrofuran (2.54 mL), stirred for 2
hours at room temperature, treated sequentially dropwise with water
(0.2 mL) and a 2 N aqueous solution of NaOH (0.6 mL), and stirred
for 1 hour. The solid was removed by filtration through a pad of
diatomaceous earth rinsing with ethyl acetate. The filtrate was
washed with water and brine, dried (MgSO.sub.4), filtered and
concentrated to give the title compound.
Example 419B
tert-butyl
4-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)-4-fluoropiperid-
ine-1-carboxylate
The title compound was prepared by substituting EXAMPLE 419A for
(tetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 387A for
4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 279A.
Example 419C
5-chloro-6-((4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide,
2*trifluoroacetic acid salt
The title compound was prepared by substituting EXAMPLE 419B for
EXAMPLE 1A in EXAMPLE 1B.
Example 419D
5-chloro-6-((1-(cyanomethyl)-4-fluoropiperidin-4-yl)methoxy)pyridine-3-sul-
fonamide
EXAMPLE 419C (0.166 g) in acetonitrile (3.00 mL) was treated with
2-chloroacetonitrile (0.027 g) and sodium carbonate (0.064 g),
heated at 60 OC overnight, cooled to room temperature and
chromatographed on silica gel with 0 to 3% methanol in
CH.sub.2C.sub.1, as eluent. The obtained solid was slurried in
water, filtered, rinsed with water and diethyl ether, and dried in
a vacuum oven at 80 OC to provide the title compound
Example 419E
N-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3--
yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 400E for
EXAMPLE 26C and EXAMPLE 419D for EXAMPLE 1F in EXAMPLE 177. .sup.1H
NMR (400 MHz, PYRIDINE-d.sub.5) 14.70 (s, 1H), 8.91 (d, 1H), 8.39
(d, 2H), 8.10 (d, 1H), 7.46 (m, 2H), 7.35 (d, 1H), 7.11 (m, 3H),
6.87 (m, 2H), 6.50 (d, 1H), 4.49 (d, 2H), 3.72 (s, 2H), 3.17 (m,
4H), 2.82 (s, 2H), 2.72 (m, 4H), 2.31 (m, 2H), 2.23 (m, 4H), 2.06
(m, 2H), 1.99 (s, 2H), 1.89 (m, 2H), 1.41 (t, 2H), 0.96 (s,
6H).
Example 420
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-chloro-6-(tetrahydrofuran-3-ylmethoxy)pyridin-3-yl]sulfonyl}-2-
-(1H-indazol-4-yloxy)benzamide
Example 420A
5-chloro-6-((tetrahydrofuran-3-yl)methoxy)pyridine-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 387A for
EXAMPLE 329A and (tetrahydrofuran-3-yl)methanol for
(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 329B.
Example 420B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-chloro-6-(tetrahydrofuran-3-ylmethoxy)pyridin-3-yl]sulfonyl}-2-
-(1H-indazol-4-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 420B for
EXAMPLE 1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 13.07 (s, 1H),
8.25 (d, 1H), 7.85 (d, 1H), 7.79 (s, 1H), 7.60 (d, 1H), 7.36 (d,
2H), 7.03-7.09 (m, 4H), 6.78 (dd, 1H), 6.51 (d, 1H), 6.13 (dd, 1H),
4.25-4.37 (m, 2H), 3.77-3.81 (m, 2H), 3.64-3.70 (m, 2H), 3.54-3.57
(m, 2H), 3.17 (br s, 4H), 2.89 (br s, 2H), 2.68-2.71 (m, 1H), 2.33
(m, 3H), 2.16-2.18 (m, 2H), 1.98-2.01 (m, 3H), 1.66-1.71 (m, 1H),
1.41 (t, 2H), 0.94 (s, 6H).
Example 421
Trans-N-({5-chloro-6-[(4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indazol-4-yloxy)benzamide
Example 421A
6-((trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)methoxy)-5-chloropyridi-
ne-3-sulfonamide
The title compound was prepared by substituting EXAMPLE 387A for
EXAMPLE 329A and
trans-4-(tert-butyldimethylsilyloxy)cyclohexylmethanol, synthesized
according to the procedure reported in WO 2008/124878 (Page 100),
for (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 329B.
Example 421B
Trans-N-({5-chloro-6-[(4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indazol-4-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 421A for
EXAMPLE 1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177, after
removal of the tert-butyldimethylsilyl group with trifluoroacetic
acid. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta.
13.12 (s, 1H), 8.29 (d, 1H), 7.88 (d, 1H), 7.84 (s, 1H), 7.40 (d,
2H), 7.07-7.13 (m, 4H), 6.83 (dd, 1H), 6.56 (s, 1H), 6.17 (d, 1H),
4.58 (d, 1H), 4.21 (d, 2H), 3.22 (br s, 4H), 2.36-2.40 (m, 3H),
2.20-2.24 (m, 2H), 2.02-2.03 (m, 2H), 1.75-1.89 (m, 5H), 1.45 (t,
2H), 1.11-1.21 (m, 4H), 0.98 (s, 6H).
Example 422
N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3-y-
l)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methy-
l}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide
Example 422A
(R)-tert-butyl
3-(3-chloro-5-sulfamoylpyridin-2-yloxy)pyrrolidine-1-carboxylate
The title compound was prepared by substituting (R)-tert-butyl
3-hydroxypyrrolidine-1-carboxylate for
(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 387B.
Example 422B
(R)-5-chloro-6-(pyrrolidin-3-yloxy)pyridine-3-sulfonamideHydrochloride
salt
Example 422A
480 mg) was dissolved in anhydrous tetrahydrofuran (10 mL
followed by addition of hydrogen chloride in dioxane solution (4M,
2.5 mL). The reaction mixture was stirred at room temperature
overnight. The solvent was removed under vacuum to provide the
title compound.
Example 422C
(R)-5-chloro-6-(1-(2,2-difluoroethyl)pyrrolidin-3-yloxy)pyridine-3-sulfona-
mide
A reaction mixture of EXAMPLE 422B (353 mg),
1,1-difluoro-2-iodoethane (268 mg) and Na.sub.2CO.sub.3 (283 mg) in
N,N-dimethylformamide (10 mL) was heated at 80.degree. C.
overnight. The reaction mixture was cooled to room temperature and
diluted with ethyl acetate. The organic phase was washed with water
and brine, dried over anhydrous sodium sulfate, and concentrated.
The crude material was purified with 2.5-3%
methanol/dichloromethane to afford the title compound.
Example 422D
N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3-y-
l)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methy-
l}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 400E for
EXAMPLE 26C and EXAMPLE 422C for EXAMPLE 1F in EXAMPLE 177. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 12.98 (s, 1H),
8.17 (d, 1H), 7.80 (d, 1H), 7.73 (s, 1H), 7.66 (d, 1H), 7.35 (d,
2H), 7.05 (m, 4H), 6.73 (m, 1H), 6.41 (d, 1H), 6.10 (m, 2H), 5.37
(m, 1H), 2.92 (m, 11H), 2.56 (m, 2H), 2.24 (m, 7H), 1.99 (m, 2H),
1.82 (m, 1H), 1.39 (m, 2H), 0.93 (s, 6H).
Example 423
2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)mo-
rpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide
Example 423A
(S)-tert-Butyl
2-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)morpholine-4-carboxylate
This EXAMPLE was prepared by substituting (S)-tert-butyl
2-(hydroxymethyl)morpholine-4-carboxylate for
4-hydroxymethyl-tetrahydropyran in EXAMPLE 387B.
Example 423B
(S)-5-chloro-6-(morpholin-2-ylmethoxy)pyridine-3-sulfonamide
This EXAMPLE was prepared by substituting EXAMPLE 423A for EXAMPLE
415A in EXAMPLE 415B.
Example 423C
(S)-5-chloro-6-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methoxy)pyridin-
e-3-sulfonamide
To a solution of EXAMPLE 423B (0.32 g) in anhydrous
N,N-dimethylformamide (10 mL) was added sodium carbonate (0.165 g)
and 2-(dimethylamino)acetyl chloride hydrochloride (0.40 g). After
stirred at ambient temperature overnight, the mixture was
concentrated to dryness. The residue was mixed with 5% aqueous
Na.sub.2CO.sub.3 (20 mL) and extracted with ethyl acetate. The
crude product was purified on a silica gel column eluting with 10%
methanol in dichloromethane saturated with ammonia to give the
title compound.
Example 423D
2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)mo-
rpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 423C for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.08 (d, 1H), 8.60 (t, 1H), 8.57 (s, 1H), 8.01 (d, 1H),
7.53 (d, 1H), 7.43 (d, 2H), 7.25 (m, 2H), 7.15 (m, 1H), 7.07 (d,
2H), 6.73-6.69 (m, 2H), 4.86-4.36 (m, 4H), 4.05-3.90 (m, 1H), 3.88
(d, 1H), 3.62-3.18 (m, 4H), 3.04 (m, 4H), 2.87 (t, 1H), 2.77 (s,
2H), 2.33 (m, 6H), 2.26 (m, 2H), 2.15 (m, 4H), 1.97 (s, 2H), 1.39
(t, 2H), 0.94 (s, 6H).
Example 424
2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)mo-
rpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide
Example 424A
(R)-tert-butyl
2-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)morpholine-4-carboxylate
This EXAMPLE was prepared by substituting (R)-tert-butyl
2-(hydroxymethyl)morpholine-4-carboxylate for
4-hydroxymethyl-tetrahydropyran in EXAMPLE 387B.
Example 424B
(R)-5-chloro-6-(morpholin-2-ylmethoxy)pyridine-3-sulfonamide
This EXAMPLE was prepared by substituting EXAMPLE 424A for EXAMPLE
415A in EXAMPLE 415B.
Example 424C
(R)-5-chloro-6-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methoxy)pyridin-
e-3-sulfonamide
This EXAMPLE was prepared by substituting EXAMPLE 424B for EXAMPLE
423B in EXAMPLE 423C.
Example 424D
2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2R)-4-(N,
N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(-
4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benza-
mide
This EXAMPLE was prepared by substituting EXAMPLE 424C for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.08 (d, 1H), 8.60 (t, 1H), 8.57 (s, 1H), 8.01 (d, 1H),
7.53 (d, 1H), 7.43 (d, 2H), 7.25 (m, 2H), 7.15 (m, 1H), 7.07 (d,
2H), 6.73-6.69 (m, 2H), 4.86-4.36 (m, 4H), 4.05-3.90 (m, 1H), 3.88
(d, 1H), 3.62-3.18 (m, 4H), 3.04 (m, 4H), 2.87 (t, 1H), 2.77 (s,
2H), 2.33 (m, 6H), 2.26 (m, 2H), 2.15 (m, 4H), 1.97 (s, 2H), 1.39
(t, 2H), 0.94 (s, 6H).
Example 425
N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-
-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]m-
ethyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 400E for EXAMPLE
1E and EXAMPLE 423C for EXAMPLE 1F in EXAMPLE 1G, and was purified
by reverse-phase HPLC using a Waters Preparative LC4000 system with
Phenomenex Luna C18 column and a water-acetonitrile mobile phase
buffered with ammonium acetate. .sup.1H NMR (500 MHz,
pyridine-d.sub.5) .delta. 8.87 (dd, 1H), 8.40 (t, 2H), 8.13 (dd,
1H), 7.46 (d, 2H), 7.35 (d, 1H), 7.15-7.10 (m, 3H) 6.87 (d, 1H),
6.85 (s, 1H), 6.50 (dd, 1H), 4.84-4.46 (m, 4H), 4.02-3.90 (m, 1H),
3.88 (m, 1H), 3.60-3.33 (m, 2H), 3.25-3.15 (m, 6H), 2.89-2.84 (m,
1H), 2.83 (s, 2H), 2.32-2.23 (m, 12H), 1.99 (s, 2H), 1.41 (t, 2H),
0.96 (s, 6H).
Example 426
Gary Wang
N-[(5-chloro-6-({[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridi-
n-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]-
methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 400E for EXAMPLE
1E and EXAMPLE 424C for EXAMPLE 1F in EXAMPLE 1G, and was purified
by reverse-phase HPLC using a Waters Preparative LC4000 system with
Phenomenex Luna C18 column and a water-acetonitrile mobile phase
buffered with ammonium acetate. .sup.1H NMR (500 MHz,
pyridine-d.sub.5) .delta. 8.87 (dd, 1H), 8.40 (t, 2H), 8.13 (dd,
1H), 7.46 (d, 2H), 7.35 (d, 1H), 7.15-7.10 (m, 3H), 6.87 (d, 1H),
6.85 (s, 1H), 6.50 (dd, 1H), 4.84-4.46 (m, 4H), 4.02-3.90 (m, 1H),
3.88 (m, 1H), 3.60-3.33 (m, 2H), 3.25-3.15 (m, 6H), 2.89-2.84 (m,
1H), 2.83 (s, 2H), 2.32-2.23 (m, 12H), 1.99 (s, 2H), 1.41 (t, 2H),
0.96 (s, 6H).
Example 427
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfony-
l}-2-(1H-indazol-4-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 387B for
EXAMPLE 1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 13.09 (s, 1H),
8.27 (d, 1H), 7.85 (d, 1H), 7.80 (s, 1H), 7.59 (d, 1H), 7.36 (d,
2H), 7.03-7.10 (m, 4H), 6.79 (dd, 1H), 6.52 (d, 1H), 6.13 (d, 1H),
4.27 (d, 2H), 3.88 (dd, 2H), 3.19 (br s, 4H), 2.91 (br s, 2H),
2.36-2.40 (br, 3H), 2.18 (m, 2H), 2.05 (m, 1H), 1.98 (s, 2H),
1.64-1.68 (m, 2H), 1.34-1.43 (m, 4H), 1.11-1.21 (m, 4H), 0.94 (s,
6H).
Example 428
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin-3-
-yl]amino}-3-nitrophenyl)sulfonyl]benzamide
Example 428A
8-{4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enylmethyl]piperazin-1-yl}-
-6-oxa-2, 11a-diazadibenzo[c,d,g]azulen-11-one
A solution of EXAMPLE 403G (4.5 g) in anhydrous dichloromethane
(100 mL) was cooled in an ice bath and catalytic
N,N-dimethylformamide was added. This was followed by the dropwise
addition of a solution of oxalyl dichloride (1.231 mL) in anhydrous
methylene chloride (5 mL). The ice bath was removed and the
reaction stirred for 1 hour while warming to ambient temperature.
The reaction was quenched by the addition of ice (150 mL) and
saturated sodium bicarbonate solution (100 mL). The mixture was
further diluted with saturated sodium bicarbonate solution (200 mL)
and methylene chloride (200 mL). The organic layer was purified on
silica gel, and was eluted with a 0, 10, 25, and 100% ethyl acetate
in methylene chloride step gradient to provide the title
compound.
Example 428B
(R)-tert-butyl
3-(2-nitro-4-sulfamoylphenylamino)pyrrolidine-1-carboxylate
To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate
(1.0 g), tetrahydrofuran (50 ml), N-ethyl-N-isopropylpropan-2-amine
(5.61 mL) and N,N-dimethylformamide (10 mL) was added
4-fluoro-3-nitrobenzenesulfonamide (1.212 g) and the mixture was
stirred for 18 hours. The crude product was isolated by
concentration and was the material was purified on silica gel, and
was eluted with a 30, 50, and 75% ethyl acetate in hexane step
gradient to provide the title compound.
Example 428C
(R)-3-nitro-4-(pyrrolidin-3-ylamino)benzenesulfonamide
A suspension of EXAMPLE 428B (2.018 g) in anhydrous dichloromethane
(25 mL) was cooled in an ice bath and 2,2,2-trifluoroacetic acid
(20 mL) was added. After stirring 15 minutes, the ice bath was
removed and the reaction was allowed to come to ambient temperature
over 2 hours. The reaction mixture was concentrated and the residue
was dissolved in water and basified with aqueous sodium carbonate
solution. The mixture was extracted repeatedly with 10% methanol in
methylene chloride and the organics were concentrated to provide
the title compound.
Example 428D
(R)-4-(1-(cyanomethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide
To a solution of EXAMPLE 428C (440 mg) in anhydrous N,
N-dimethylformamide (10 mL) was added sodium carbonate (132 mg). To
the resulting suspension was added 2-bromoacetonitrile (0.077 mL)
and the mixture was heated at 60.degree. C. for 18 hours. The crude
material was isolated by concentration and was purified on silica
gel, and was eluted with a 0.5, 2.5, and 5% methanol in methylene
chloride step gradient to provide the title compound.
Example 428E
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin-3-
-yl]amino}-3-nitrophenyl)sulfonyl]benzamide
To a solution of EXAMPLE 428D (82.6 mg) in tetrahydrofuran (7 mL)
was added 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.063
mL). This mixture was stirred at ambient temperature for 45 minutes
and a solution of EXAMPLE 428A (117 mg) in tetrahydrofuran (3 mL)
was added. After stirring 18 hours, the crude product was isolated
by concentration and was purified by reverse phase chromatography
with ammonium acetate buffer in acetonitrile to give the title
compound. .sup.1H NMR (400 MHz, pyridine-d.sub.5) .delta. 9.27 (d,
1H), 8.59 (s, 1H), 8.55 (d, 1H), 8.40 (dd, 1H), 7.99 (d, 1H), 7.54
(m, 1H), 7.43 (d, 2H), 7.25 (m, 1H), 7.16 (m, 1H), 7.07 (d, 2H),
6.86 (d, 1H), 6.69 (m, 2H), 5.73 (m, 2H), 4.15 (m, 1H), 3.90 (s,
2H), 3.03 (m, 4H), 2.96-287. (m, 2H), 2.81-2.76 (m. 3H), 2.58 (m,
1H), 2.32-2.23 (m, 3H), 2.14 (m, 4H), 1.97 (s, 2H), 1.73 (m, 1H),
1.38 (t, 2H), 0.94 (s, 6H).
Example 429
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethyl-
]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}benzamide
Example 429A
(R)-4-(1-(2-(2-methoxyethoxy)ethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesul-
fonamide
The title compound was prepared by substituting
1-bromo-2-(2-methoxyethoxy)ethane for 2-bromoacetonitrile in
EXAMPLE 428D.
Example 429B
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethyl-
]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}benzamide
The title compound was prepared by substituting EXAMPLE 429A for
EXAMPLE 428D in EXAMPLE 428E. .sup.1H NMR (400 MHz,
pyridine-d.sub.5) .delta. 9.26 (d, 1H), 8.58 (m, 2H), 8.38 (dd,
1H), 8.01 (d, 1H), 7.53 (d, 1H), 7.43 (d, 2H), 7.25 (d, 1H), 7.16
(d, 1H), 7.07 (d, 2H), 6.85 (d, 1H), 6.71-6.69 (m, 2H), 5.33 (m,
2H), 4.05 (m, 1H), 3.63 (m, 4H), 3.54 (m, 2H), 3.29 (s, 3H), 3.03
(m, 4H), 2.86 (m, 1H), 2.77 (m, 4H), 2.70 (t, 2H), 2.38 (m, 1H),
2.27-2.18 (m, 3H), 2.14 (m, 4H), 1.97 (s, 2H), 1.64 (m, 1H), 1.38
(t, 2H), 0.94 (s, 6H).
Example 430
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrro-
lidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide
Example 430A
R)-4-(1-(2-(dimethylamino)acetyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfo-
namide
The title compound was prepared by substituting
2-(dimethylamino)acetyl chloride for 2-bromoacetonitrile in EXAMPLE
428D.
Example 430B
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrro-
lidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide
The title compound was prepared by substituting EXAMPLE 430A for
EXAMPLE 428D in EXAMPLE 428E. .sup.1H NMR (400 MHz,
pyridine-d.sub.5) .delta. 9.25 (m, 1H), 8.59 (d, 1H), 8.47-8.35 (m,
2H), 8.01 (d, 1H), 7.54 (d, 1H), 7.44 (d, 2H), 7.25-7.20 (m, 2H),
7.16-6.92 (m, 4H), 6.71 (m, 2H), 5.55 (m, 1H), 4.34-4.18 (m, 1H),
4.03 (m, 1H), 3.84-3.63 (m, 3H), 3.44-3.34 (m, 2H), 3.03 (m, 4H),
2.77 (s, 2H), 2.43 (m, 6H), 2.25 (m, 3H), 2.14 (m, 4H), 2.03-1.83
(m, 3H), 1.38 (t, 2H), 0.94 (s, 6H).
Example 431
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]m-
ethyl}amino)-3-nitrophenyl]sulfonyl}benzamide
Example 431A
4-((4-(cyanomethyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide
This EXAMPLE was prepared by substituting 2-bromo-acetonitrile for
2, 2-difluoroethyl iodide in EXAMPLE 415C at ambient
temperature.
Example 431B
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]m-
ethyl}amino)-3-nitrophenyl]sulfonyl}benzamide
This EXAMPLE was prepared by substituting EXAMPLE 431A for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.25 (d, 1H), 8.87 (t, 1H), 8.58 (s, 1H), 8.38 (dd, 1H),
8.00 (d, 1H), 7.53 (d, 1H), 7.43 (d, 2H), 7.25 (m, 2H), 7.16 (d,
1H), 7.07 (d, 2H), 6.97 (d, 1H), 6.73-6.68 (m, 2H), 3.96-3.85 (m,
2H), 3.78 (s, 2H), 3.66 (dt, 1H), 3.53-3.42 (m, 2H), 3.03 (m, 4H),
2.90 (d, 1H), 2.76 (s, 2H), 2.61 (d, 1H), 2.51 (dt, 1H), 2.40 (t,
1H), 2.25 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.38 (t, 2H), 0.94
(s, 6H).
Example 432
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)met-
hyl]amino}-3-nitrophenyl)sulfonyl]benzamide
Example 432A
4-((4-cyclopropylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide
A solution of EXAMPLE 415B (0.633 g) and
(1-ethoxycyclopropoxy)trimethylsilane (1.601 ml) in anhydrous
methanol (15 mL) and acetic acid (1.7 ml) was refluxed for 30
minutes and allowed to cool to room temperature. Sodium
cyanoborohydride (0.377 g) was then added and the mixture was
stirred at ambient temperature overnight. The reaction mixture was
concentrated to dryness. The residue was mixed with 5% aqueous
Na.sub.2CO.sub.3 solution (25 mL) and extracted with ethyl acetate.
The crude product was purified on a silica gel column eluting with
5% and 10% methanol in dichloromethane to provide the title
compound.
Example 432B
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)met-
hyl]amino}-3-nitrophenyl)sulfonyl]benzamide
This EXAMPLE was prepared by substituting EXAMPLE 432A for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.25 (d, 1H), 8.89 (t, 1H), 8.57 (s, 1H), 8.38 (dd, 1H),
8.00 (d, 1H), 7.53 (d, 1H), 7.43 (d, 2H), 7.25 (m, 2H), 7.16 (d,
1H), 7.07 (d, 2H), 6.98 (d, 1H), 6.73-6.68 (m, 2H), 3.90-3.83 (m,
2H), 3.60 (dt, 1H), 3.55-3.41 (m, 2H), 3.03 (m, 4H), 2.96 (d, 1H),
2.76 (s, 2H), 2.69 (d, 1H), 2.35 (dt, 1H), 2.26-2.20 (m, 3H), 2.14
(m, 4H), 1.97 (s, 2H), 1.59 (m, 1H), 1.38 (t, 2H), 0.94 (s, 6H),
0.47-0.37 (m, 4H).
Example 433
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-oxetan-3-ylmorpholin--
2-yl)methyl]amino}phenyl)sulfonyl]benzamide
Example 433A
3-nitro-4-((4-(oxetan-3-yl)morpholin-2-yl)methylamino)benzenesulfonamide
This EXAMPLE was prepared by substituting oxetan-3-one for
(1-ethoxycyclopropoxy)-trimethylsilane in EXAMPLE 432A.
Example 433B
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-oxetan-3-ylmorpholin--
2-yl)methyl]amino}phenyl)sulfonyl]benzamide
This EXAMPLE was prepared by substituting EXAMPLE 433A for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.25 (d, 1H), 8.87 (t, 1H), 8.57 (s, 1H), 8.38 (dd, 1H),
8.02 (d, 1H), 7.53 (d, 1H), 7.44 (d, 2H), 7.24 (m, 2H), 7.13 (d,
1H), 7.07 (d, 2H), 6.98 (d, 1H), 6.73-6.68 (m, 2H), 4.69-4.62 (m,
4H), 3.98-3.88 (m, 2H), 3.69 (dt, 1H), 3.55-3.35 (m, 3H), 3.03 (m,
4H), 2.77 (s, 2H), 2.74 (d, 1H), 2.44 (d, 1H), 2.25 (m, 2H), 2.14
(m, 4H), 1.97 (s, 2H), 1.94 (m, 1H), 1.87 (t, 1H), 1.38 (t, 2H),
0.94 (s, 6H).
Example 434
N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}ox-
y)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1--
en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide
Example 434A
(R)-5-chloro-6-(1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yloxy)pyridine-3-s-
ulfonamide
EXAMPLE 422B (278 mg) and 1,3-difluoropropan-2-one (94 mg) were
suspended in dichloroethane (10 ml). N,N-dimethylformamide (1.5 mL)
was added drop wise until a white milky suspension formed. The
reaction mixture was stirred at room temperature for 15 minutes
followed by the addition of sodium triacetoxyborohydride (424 mg).
The reaction mixture was stirred at room temperature overnight. The
solvent was removed under vacuum, and the crude material was
purified with 2.5-5% methanol/dichloromethane to afford the title
compound.
Example 434B
N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}ox-
y)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1--
en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide
The title compound was prepared by substituting EXAMPLE 400E for
EXAMPLE 26C and EXAMPLE 434A for EXAMPLE 1F in EXAMPLE 177. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 12.96 (s, 1H),
8.16 (d, 1H), 7.79 (m, 1H), 7.69 (m, 2H), 7.35 (d, 2H), 7.05 (m,
4H), 6.72 (m, 1H), 6.39 (d, 1H), 6.09 (dd, 3.05 Hz, 1H), 5.37 (m,
1H), 4.66 (t, 2H), 4.54 (t, 2H), 2.91 (m, 12H), 2.23 (m, 7H), 1.97
(s, 2H), 1.82 (m, 1H), 1.40 (t, 2H), 0.93 (s, 6H).
Example 435
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino-
)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide
Example 435A
(R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-amine
To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (0.500 g)
and 1,3-difluoropropan-2-one (0.278 g) in dichloromethane (5 mL)
was added sodium triacetoxyborohydride (0.853 g). After stirring
for one hour, the reaction was quenched with saturated aqueous
NaHCO.sub.3 solution (5 mL). The mixture was extracted with
dichloromethane (25 mL), and the organic layer was dried over
anhydrous magnesium sulfate, filtered, and concentrated. The
resulting residue was treated with HCl (4.0M in 1,4-dioxane, 4 mL)
and methanol (1 mL) and stirred for one hour. The mixture was
concentrated to give the title compound.
Example 435B
(R)-4-(1-(1,3-difluoropropan-2-yl)pyrrolidin-3-ylamino)-3-nitrobenzenesulf-
onamide
To 4-fluoro-3-nitrobenzenesulfonamide (0.272 g) and EXAMPLE 435A
(0.195 g) in tetrahydrofuran (3.0 mL) was added
N-ethyl-N-isopropylpropan-2-amine (0.512 mL) and the reaction
stirred at room temperature. After stirring for six hours, the
reaction was concentrated, loaded onto silica gel (Reveleris 40 g)
and the product eluted using a gradient of 25-100% ethyl
acetate/hexanes over 30 minutes to give the title compound.
Example 435C
4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1--
yl}-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-4-yloxy]-benzoic
acid methyl ester
EXAMPLE 400D (1000 mg) was dissolved in N,N-dimethylformamide (12
mL) and sodium hydride (60% in mineral oil, 45 mg) was added. The
solution was stirred at room temperature for 15 minutes,
2-(trimethylsilyl)ethoxymethyl chloride (299 mg) was added, and the
solution was stirred at room temperature for 45 minutes. The
solution was added to water and extracted with ethyl acetate. The
extract was washed with brine, dried on anhydrous sodium sulfate,
filtered, concentrated and purified by flash column chromatography
on silica gel using 30-50% ethyl acetate in hexanes.
Example 435D
4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1--
yl}-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-4-yloxy]-benzoic
acid
This example was prepared by substituting EXAMPLE 435C for EXAMPLE
1D in EXAMPLE 1E.
Example 435E
N-{4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-
-1-yl}-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-4-yloxy]-benzoyl}-
-4-[(R)-1-(2-fluoro-1-fluoromethyl-ethyl)-pyrrolidin-3-ylamino]-3-nitro-be-
nzenesulfonamide
This example was prepared by substituting EXAMPLE 435D for EXAMPLE
1E and EXAMPLE 435B for EXAMPLE 1F in EXAMPLE 1G.
Example 435F
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino-
)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide
EXAMPLE 435E (103 mg) was dissolved in trifluoroacetic acid (1.8
mL) and water (0.2 mL) and stirred at room temperature for 90
minutes. The solvents were removed under vacuum, the residue
dissolved in 1,4-dioxane (2 mL) and treated with 1M sodium
hydroxide (1 mL), and the solution stirred at room temperature for
30 minutes. The solution was added to a saturated aqueous sodium
bicarbonate solution and extracted with dichloromethane. The
extract was washed with brine, dried on anhydrous sodium sulfate,
filtered, and the solvent removed under vacuum. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 13.09 (bs, 1H), 8.37 (m,
2H), 7.84 (d, 1H), 7.58-7.45 (m, 2H), 7.36 (d, 2H), 7.17-7.03 (m,
4H), 6.95 (dd, 1H), 6.84-6.76 (m, 1H), 6.53 (dd, 1H), 6.17 (t, 1H),
4.72 (d, 2H), 4.56 (d, 2H), 4.23 (m, 1H), 3.17 (m, 4H), 3.12-3.03
(m, 2H), 3.02-2.91 (m, 2H), 2.86-2.73 (m, 4H), 2.40-2.14 (m, 6H),
1.97 (bs, 2H), 1.70 (m, 1H), 1.40 (t, 2H), 0.94 (s, 6H).
Example 436
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-
-(1H-indazol-4-yloxy)benzamide
Example 436A
4-(1-cyclopropyl-piperidin-4-ylamino)-3-nitro-benzenesulfonamide
This example was prepared by substituting
1-cyclopropyl-piperidin-4-ylamine for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A.
Example 436B
N-{4-{4-[2-(4-chlorophenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin--
1-yl}-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-4-yloxy]-benzoyl}--
4-(1-cyclopropyl-piperidin-4-ylamino)-3-nitro-benzenesulfonamide
This example was prepared by substituting EXAMPLE 435D for EXAMPLE
1E and EXAMPLE 436A for EXAMPLE 1F in EXAMPLE 1G.
Example 436C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-
-(1H-indazol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 436B for EXAMPLE
435E in EXAMPLE 435F. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 13.05 (bs, 1H), 8.35 (d, 1H),
8.17 (d, 1H), 7.77 (bs, 1H), 7.57 (td, 2H), 7.35 (d, 2H), 7.09-7.03
(m, 4H), 6.98 (d, 1H), 6.77 (dd, 1H), 6.48 (bs, 1H), 6.17 (m, 1H),
3.66 (m, 1H), 3.12 (bs, 4H), 2.92 (m, 2H), 2.76 (bs, 2H), 2.21 (m,
8H), 1.97 (bs, 2H), 1.94 (m, 2H), 1.73 (m, 1H), 1.55 (m, 2H), 1.40
(t, 2H), 0.93 (s, 6H), 0.46 (d, 2H), 0.35 (bs, 2H).
Example 437
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)morp-
holin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide
Example 437A
(R)-tert-butyl
2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxylate
This example was prepared by substituting (R)-tert-butyl
2-(aminomethyl)morpholine-4-carboxylate for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 437B
(S)-4-(morpholin-2-ylmethylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting EXAMPLE 437A for EXAMPLE
415A in EXAMPLE 415B.
Example 437C
(R)-4-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methylamino)-3-nitrobenz-
enesulfonamide
This example was prepared by substituting EXAMPLE 437B for EXAMPLE
423B in EXAMPLE 423C.
Example 437D
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)morp-
holin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide
This example was prepared by substituting EXAMPLE 437C for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.25 (s, 1H), 8.86 (t, 1H), 8.57 (s, 1H), 8.38 (t, 1H),
8.02 (d, 1H), 7.53 (d, 1H), 7.44 (d, 2H), 7.24 (m, 2H), 7.13 (d,
1H), 7.07 (d, 2H), 6.97 (dd, 1H), 6.73-6.68 (m, 2H), 4.75, 4.50
(dd, 1H), 4.33, 4.02 (dd, 1H), 3.93 (m, 1H), 3.85-3.70 (m, 1H),
3.65-3.40 (m, 3H), 3.33 (dd, 1H), 3.25-3.10 (m, 2H), 3.03 (m, 4H),
2.90 (m, 1H), 2.77 (s, 2H), 2.27-2.25 (m, 8H), 2.14 (m, 4H), 1.97
(s, 2H), 1.38 (t, 2H), 0.94 (s, 6H).
Example 438
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)morp-
holin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide
Example 438A
(S)-tert-butyl
2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxylate
This example was prepared by substituting (S)-tert-butyl
2-(aminomethyl)morpholine-4-carboxylate for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 438B
(R)-4-(morpholin-2-ylmethylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting EXAMPLE 438A for EXAMPLE
415A in EXAMPLE 415B.
Example 438C
(S)-4-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methylamino)-3-nitrobenz-
enesulfonamide
This example was prepared by substituting EXAMPLE 438B for EXAMPLE
423B in EXAMPLE 423C.
Example 438D
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)morp-
holin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide
This example was prepared by substituting EXAMPLE 438C for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.25 (s, 1H), 8.86 (t, 1H), 8.57 (s, 1H), 8.38 (t, 1H),
8.02 (d, 1H), 7.53 (d, 1H), 7.44 (d, 2H), 7.24 (m, 2H), 7.13 (d,
1H), 7.07 (d, 2H), 6.97 (dd, 1H), 6.73-6.68 (m, 2H), 4.75, 4.50
(dd, 1H), 4.33, 4.02 (dd, 1H), 3.93 (m, 1H), 3.85-3.70 (m, 1H),
3.65-3.40 (m, 3H), 3.33 (dd, 1H), 3.25-3.10 (m, 2H), 3.03 (m, 4H),
2.90 (m, 1H), 2.77 (s, 2H), 2.27-2.25 (m, 8H), 2.14 (m, 4H), 1.97
(s, 2H), 1.38 (t, 2H), 0.94 (s, 6H).
Example 439
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmeth-
yl)amino]phenyl}sulfonyl)benzamide
Example 439A
3-nitro-4-((tetrahydrofuran-3-yl)methylamino)benzenesulfonamide
This example was prepared by substituting
(tetrahydrofuran-3-yl)methylamine for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 439B
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmeth-
yl)amino]phenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 439A for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.26 (d, 1H), 8.70 (t, 1H), 8.57 (s, 1H), 8.40 (dd, 1H),
8.01 (d, 1H), 7.51 (d, 1H), 7.44 (d, 2H), 7.24 (m, 2H), 7.14 (d,
1H), 7.07 (d, 2H), 6.89 (d, 1H), 6.73-6.68 (m, 2H), 3.93-3.89 (m,
1H), 3.83 (dd, 1H), 3.83-3.68 (m, 2H), 3.33-3.23 (m, 2H), 3.03 (m,
4H), 2.77 (s, 2H), 2.55-2.50 (m, 1H), 2.25 (m, 2H), 2.14 (m, 4H),
2.00-1.93 (m, 3H), 1.65-1.58 (m, 1H), 1.38 (t, 2H), 0.94 (s,
6H).
Example 440
Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcy-
clohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methy-
l]amino}-3-nitrophenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 311B for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.29 (d, 1H), 8.67 (t, 1H), 8.59 (s, 1H), 8.41 (dd, 1H),
7.99 (d, 1H), 7.52 (d, 1H), 7.43 (d, 2H), 7.24 (m, 1H), 7.17 (m,
1H), 7.07 (d, 2H), 6.90 (d, 1H), 6.72-6.68 (m, 2H), 5.97 (m, 2H),
3.29 (s, 3H), 3.14 (t, 2H), 3.02 (m, 5H), 2.76 (s, 2H), 2.25 (m,
2H), 2.13 (m, 4H), 2.07 (m, 2H), 1.97 (s, 2H), 1.82 (m, 2H), 1.57
(m, 1H), 1.38 (t, 2H), 1.22 (m, 2H), 1.01 (m, 2H), 0.94 (s,
6H).
Example 441
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-y-
l)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 409D for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.27 (d, 1H), 8.84 (t, 1H), 8.57 (s, 1H), 8.41 (dd, 1H),
7.99 (d, 1H), 7.52 (d, 1H), 7.43 (d, 2H), 7.23 (m, 1H), 7.15 (m,
1H), 7.14-7.02 (m, 3H), 6.70 (m, 2H), 6.49 (m, 2H), 3.86 (m, 2H),
3.76-3.69 (m, 3H), 3.65 (d, 1H), 3.03 (m, 4H), 2.76 (s, 2H), 2.25
(m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.92-1.76 (m, 4H), 1.38 (t,
2H), 0.94 (s, 6H).
Example 442
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-p-
yran-4-yl)methoxy]pyridin-3-yl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 416D for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.02 (d, 1H), 8.59 (s, 1H), 8.35 (m, 1H), 8.01 (d, 1H),
7.51 (d, 1H), 7.44 (d, 2H), 7.22 (m, 2H), 7.12 (d, 1H), 7.07 (d,
2H), 6.84 (m, 1H), 6.73 (m, 2H), 4.59 (s, 1H), 4.54 (s, 1H),
3.89-3.74 (m, 4H), 3.05 (m, 4H), 2.78 (s, 2H), 2.26 (m, 2H), 2.16
(m, 4H), 2.02-1.81 (m, 6H), 1.39 (t, 2H), 0.94 (s, 6H).
Example 443
2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-
-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide
This example was prepared by substituting EXAMPLE 404A for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.12 (d, 1H), 8.68 (d, 1H), 8.59 (s, 1H), 7.99 (d, 1H),
7.52 (d, 1H), 7.44 (d, 2H), 7.24 (d, 1H), 7.15 (d, 1H), 7.07 (d,
2H), 6.73-6.69 (m, 3H), 6.56 (m, 1H), 4.56 (s, 1H), 4.51 (s, 1H),
3.91-3.76 (m, 4H), 3.04 (m, 4H), 2.77 (s, 2H), 2.26 (m, 2H), 2.15
(m, 4H), 1.99-1.85 (m, 6H), 1.39 (t, 2H), 0.94 (s, 6H).
Example 444
N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}me-
thoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide
Example 444A
(R)-5-chloro-6-((1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl)methoxy)pyridi-
ne-3-sulfonamide
This example was prepared by substituting EXAMPLE 445B for EXAMPLE
422B in EXAMPLE 434A.
Example 444B
N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}me-
thoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 400E for EXAMPLE
26C and EXAMPLE 444A for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 12.98 (s, 1H), 8.19
(d, 1H), 7.81 (d, 1H), 7.73 (s, 1H), 7.66 (d, 1H), 7.35 (d, 2H),
7.05 (m, 4H), 6.73 (dd, 1H), 6.42 (d, 1H), 6.10 (m, 1H), 4.64 (s,
2H), 4.54 (d, 2H), 4.24 (m, 2H), 3.07 (s, 4H), 2.89 (s, 2H), 2.74
(m, 4H), 2.56 (m, 2H), 2.20 (m, 6H), 1.98 (m, 4H), 1.54 (m, 1H),
1.40 (t, 2H), 0.91 (s, 6H).
Example 445
N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-
-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]m-
ethyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide
Example 445A
(R)-tert-butyl
3-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)pyrrolidine-1-carboxylate
This example was prepared by substituting (R)-tert-butyl
3-(hydroxymethyl)pyrrolidine-1-carboxylate for
(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 387B.
Example 445B
(R)-5-chloro-6-(pyrrolidin-3-ylmethoxy)pyridine-3-sulfonamide
This example was prepared by substituting EXAMPLE 445A for EXAMPLE
422A in EXAMPLE 422B.
Example 445C
(R)-5-chloro-6-((1-(2,2-difluoroethyl)pyrrolidin-3-yl)methoxy)pyridine-3-s-
ulfonamide
This example was prepared by substituting EXAMPLE 445B for EXAMPLE
422B in EXAMPLE 422C.
Example 445D
N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-
-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]m-
ethyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 400E for EXAMPLE
26C and EXAMPLE 445C for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 12.98 (s, 1H), 8.19
(d, 1H), 7.81 (d, 1H), 7.73 (s, 1H), 7.66 (d, 1H), 7.35 (d, 2H),
7.05 (m, 4H), 6.72 (dd, 1H), 6.41 (d, 1H), 6.10 (m, 2H), 4.23 (m,
2H), 3.07 (s, 4H), 2.82 (m, 5H), 2.62 (m, 3H), 2.24 (s, 4H), 2.17
(s, 2H), 1.94 (m, 3H), 1.53 (m, 1H), 1.40 (t, 2H), 0.93 (s,
6H).
Example 446
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-indazol-4-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]ami-
no}-3-nitrophenyl)sulfonyl]benzamide
Example 446A
2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-4-yloxy]-4-(4-((2-(4-chl-
orophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((trans-
-4-methoxycyclohexyl)methylamino)-3-nitrophenylsulfonyl)benzamide
This example was prepared by substituting EXAMPLE 435D for EXAMPLE
1E and EXAMPLE 311B for EXAMPLE 1F in EXAMPLE 1G.
Example 446B
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-(1H-indazol-4-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]ami-
no}-3-nitrophenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 446A for EXAMPLE
435E in EXAMPLE 435F. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 13.08 (bs, 1H), 8.53 (t, 1H),
8.37 (d, 1H), 7.84 (d, 1H), 7.53 (m, 2H), 7.35 (d, 2H), 7.09 (d,
2H), 7.05 (d, 2H), 6.94 (d, 1H), 6.79 (m, 1H), 6.51 (dd, 1H), 6.18
(m, 1H), 3.23 (s, 3H), 3.17-3.00 (m, 5H), 2.78 (bs, 2H), 2.30-2.13
(m, 8H), 2.02 (m, 2H), 1.97, (bs, 2H), 1.80 (m, 2H), 1.60 (m, 1H),
1.40 (t, 2H), 1.07 (m, 4H), 0.93 (s, 6H).
Example 447
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-
-4-yloxy)benzamide
Example 447A
N-{4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-
-1-yl}-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-4-yloxy]-benzoyl}-
-4-([1,4]dioxan-2-ylmethoxy)-3-nitrobenzenesulfonamide
This example was prepared by substituting EXAMPLE 435D for EXAMPLE
1E and EXAMPLE 297A for EXAMPLE 1F in EXAMPLE 1G.
Example 447B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-
-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 447A for EXAMPLE
435E in EXAMPLE 435F. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 13.04 (bs, 1H), 8.07 (bs, 1H),
7.78 (t, 2H), 7.59 (d, 1H), 7.36 (d, 2H), 7.25 (d, 1H), 7.08 (d,
2H), 7.06 (d, 2H), 6.77 (d, 1H), 6.48 (bs, 1H), 6.15 (m, 1H), 4.20
(t, 2H), 3.92-3.76 (m, 3H), 3.65 (m, 2H), 3.48 (td, 2H), 3.14 (bs,
4H), 2.80 (m, 2H), 2.38-2.13 (m, 6H), 1.97 (bs, 2H), 1.40 (t, 2H),
0.94 (s, 6H).
Example 448
N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indazol-4-yloxy)benzamide
Example 448A
5-chloro-6-(1-cyclopropyl-piperidin-4-ylamino)-pyridine-3-sulfonic
acid amide
This example was prepared by substituting
1-cyclopropyl-piperidin-4-ylamine for
1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 387A for
4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.
Example 448B
5-Chloro-6-(1-cyclopropyl-piperidin-4-ylamino)-pyridine-3-sulfonic
acid
4-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-
-yl}-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-4-yloxy]-benzoylami-
de
This example was prepared by substituting EXAMPLE 435D for EXAMPLE
1E and EXAMPLE 448A for EXAMPLE 1F in EXAMPLE 1G.
Example 448C
N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)--
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indazol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 448B for EXAMPLE
435E in EXAMPLE 435F. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 13.03 (bs, 1H), 8.18 (d, 1H),
7.79 (bs, 1H), 7.65-7.58 (m, 2H), 7.36 (d, 2H), 7.33 (m, 1H), 7.10
(d, 2H), 7.06 (d, 2H), 6.74 (dd, 1H), 6.43 (bs, 1H), 6.19 (m, 1H),
3.95 (m, 1H), 3.08 (m, 4H), 2.96 (m, 2H), 2.75 (bs, 2H), 2.37-2.10
(m, 9H), 1.97 (bs, 2H), 1.78 (m, 2H), 1.56 (m, 2H), 1.40 (t, 2H),
0.93 (s, 6H), 0.42 (d, 2H), 0.33 (bs, 2H).
Example 449
2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)a-
mino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)benzamide
Example 449A
5-chloro-6-(1-cyclopropylpiperidin-4-ylamino)pyridine-3-sulfonamide
A mixture of EXAMPLE 387A (0.4 g), 1-cyclopropylpiperidin-4-amine
(0.3 g) and N,N-diisopropylethylamine (0.37 mL) in dioxane (3 mL)
was heated at 100.degree. C. for 18 hours. The crude product was
isolated by concentration and was purified on silica gel, which was
eluted with ethyl acetate to give the title compound.
Example 449B
2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)a-
mino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)benzamide
This example was prepared by substituting EXAMPLE 449A for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.22 (m, 1H), 8.55 (s, 1H), 8.47 (s, 1H), 8.00 (d, 1H),
7.54 (d, 1H), 7.44 (d, 2H), 7.25 (m, 1H), 7.19 (m, 1H), 7.07 (d,
2H), 7.01 (m, 1H), 6.68 (m, 2H), 5.35 (m, 2H), 4.22 (m, 1H),
3.04-2.95 (m, 6H), 2.77 (s, 2H), 2.29-2.24 (m, 4H), 2.14 (m, 4H),
2.03 (m, 2H), 1.97 (s, 2H), 1.70 (m, 2H), 1.52 (m, 1H), 1.38 (t,
2H), 0.94 (s, 6H), 0.35 (m, 4H).
Example 450
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-n-
itrophenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 336A for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.55)
.delta. 9.24 (m, 1H), 8.81 (m, 1H), 8.56 (s, 1H), 8.37 (dd, 1H),
8.03 (d, 1H), 7.52 (d, 1H), 7.44 (d, 2H), 7.21 (m, 1H), 7.11 (m,
1H), 7.07 (d, 2H), 6.92 (d, 1H), 6.71 (m, 2H), 5.33 (m, 2H), 3.94
(m, 2H), 3.78 (m, 1H), 3.73-3.66 (m, 2H), 3.58 (m, 1H), 3.51-3.36
(m, 3H), 3.03 (m, 4H), 2.77 (s, 2H), 2.26 (m, 2H), 2.15 (m, 4H),
1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).
Example 451
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide
Example 451A
4-(1-cyclopropylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide
To a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.26 g) and
1-cyclopropylpiperidin-4-amine (0.802 g) in tetrahydrofuran (20 mL)
was added N,N-diisopropylethylamine (2.22 g) and
4-dimethylaminopyridine (35 mg). The mixture was heated at reflux
for 18 hours and upon cooling was diluted with ethyl acetate (200
mL) and aqueous NaHCO.sub.3. The crude product was isolated by
concentration of the organic layer and was purified on silica gel,
which was eluted with 5% methanolic ammonia in methylene chloride
to give the title compound.
Example 451B
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 451A for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.26 (m, 1H), 8.59 (s, 1H), 8.46 (d, 1H), 8.42 (dd, 1H),
8.01 (d, 1H), 7.53 (d, 1H), 7.43 (d, 2H), 7.25 (d, 1H), 7.17 (d,
1H), 7.07 (d, 2H), 6.96 (d, 1H), 6.72-6.67 (m, 2H), 5.48 (m, 2H),
3.54 (m, 1H), 3.03 (m, 4H), 2.90 (m, 2H), 2.76 (s, 2H), 2.37 (m,
2H), 2.25 (m, 2H), 2.14 (m, 4H), 1.98-1.91 (m, 4H), 1.56 (m, 3H),
1.38 (t, 2H), 0.94 (s, 6H), 0.42 (m, 4H).
Example 452
Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcy-
clohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl-
)amino]-3-nitrophenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 204A for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.27 (m, 1H), 8.59 (s, 1H), 8.42 (dd, 1H), 8.36 (d, 1H),
8.01 (d, 1H), 7.53 (d, 1H), 7.43 (d, 2H), 7.25 (m, 1H), 7.17 (m,
1H), 7.07 (d, 2H), 6.95 (d, 1H), 6.71 (d, 2H), 6.33 (m, 2H), 3.76
(m, 4H), 3.40 (m, 1H), 3.03 (m, 4H), 2.76 (s, 2H), 2.52 (m, 4H),
2.25 (m, 3H), 2.14 (m, 4H), 2.07 (m, 2H), 1.97 (m, 2H), 1.89 (m,
2H), 1.42-1.21 (m, 6H), 0.94 (s, 6H).
Example 453
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 174A for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.25 (m, 2H), 8.59 (s, 1H), 8.44 (m, 1H), 8.00 (d, 1H),
7.68 (d, 1H), 7.53 (d, 1H), 7.43 (d, 2H), 7.25 (m, 1H), 7.17 (m,
1H), 7.06 (d, 2H), 6.72-6.67 (m, 2H), 6.36 (m, 1H), 2.02 (m, 4H),
2.93 (m, 4H), 2.76 (s, 2H), 2.74-2.61 (m, 2H), 2.35-2.22 (m, 5H),
2.19 (s, 3H), 2.16-2.10 (m, 4H), 1.97 (m, 2H), 1.38 (t, 2H), 0.94
(s, 6H).
Example 454
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]a-
mino}-3-nitrophenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 88A for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.28 (m, 1H), 8.66 (m, 1H), 8.58 (s, 1H), 8.40 (dd, 1H),
8.02 (d, 1H), 7.53 (d, 1H), 7.44 (d, 2H), 7.24 (m, 1H), 7.15 (m,
1H), 7.07 (d, 2H), 6.89 (d, 1H), 6.73-6.69 (m, 2H), 5.86 (m, 2H),
3.17 (t, 2H), 3.01-3.04 (m, 4H), 2.86 (m, 2H), 2.77 (s, 2H), 2.25
(m, 5H), 2.14 (m, 4H), 1.96-1.97 (s, 2H), 1.92 (m, 2H), 1.70 (m,
2H), 1.60 (m, 1H), 1.48-1.37 (m, 4H), 0.94 (s, 6H).
Example 455
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({(2R)-4-[2-(2-methoxyethoxy)ethy-
l]morpholin-2-yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide
Example 455A
(R)-4-((4-(2-(2-methoxyethoxy)ethyl)morpholin-2-yl)methylamino)-3-nitroben-
zenesulfonamide
This example was prepared by substituting EXAMPLE 437B for EXAMPLE
415B and 2-(2-methoxyethoxy)ethyl bromide for 2,2-difluoroethyl
iodide in EXAMPLE 415C.
Example 455B
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({(2R)-4-[2-(2-methoxyethoxy)ethy-
l]morpholin-2-yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide
This example was prepared by substituting EXAMPLE 455A for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.24 (d, 1H), 8.85 (t, 1H), 8.56 (s, 1H), 8.36 (dd, 1H),
8.03 (d, 1H), 7.51 (d, 1H), 7.44 (d, 2H), 7.24 (m, 2H), 7.12 (d,
1H), 7.07 (d, 2H), 6.91 (d, 1H), 6.73-6.68 (m, 2H), 3.93-3.86 (m,
2H), 3.72-3.61 (m, 5H), 3.53 (m. 2H), 3.48-3.40 (m, 2H), 3.28 (s,
3H), 3.03 (m, 4H), 2.95 (d, 1H), 2.77 (s, 2H), 2.70 (d, 1H), 2.69
(t, 2H), 2.27-2.10 (m, 8H), 1.97 (s, 2H), 1.38 (t, 2H), 0.94 (s,
6H).
Example 456
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]a-
mino}-3-nitrophenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 412C for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.29 (d, 1H), 8.73 (t, 1H), 8.58 (s, 1H), 8.42 (dd, 1H),
7.99 (d, 1H), 7.52 (d, 1H), 7.43 (d, 2H), 7.24 (m, 2H), 7.17 (d,
1H), 7.07 (d, 2H), 6.94 (d, 1H), 6.72 (d, 1H), 6.69 (dd, 1H), 3.22
(t, 2H), 3.03 (m, 4H), 2.76 (s, 2H), 2.25 (m, 2H), 2.13 (m, 6H),
1.97 (s, 2H), 1.85-1.70 (m, 5H), 1.38 (t, 2H), 1.36-1.33 (m, 2H),
0.94 (s, 6H).
Example 457
N-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1-
H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-e-
n-1-yl]methyl}piperazin-1-yl)benzamide
Example 457A
4-((4-acetylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide
A solution of EXAMPLE 415B (145 mg) and
N-ethyl-N-isopropylpropan-2-amine (120 .mu.l) in anhydrous
dichloromethane (5 mL) and N,N-dimethylformamide (2 mL) was cooled
with an ice bath and acetic anhydride (56 .mu.l) was added
dropwise. The mixture was stirred at room temperature for 3 hours
and concentrated to dryness. The residue was triturated with water.
The resulting solid was dried under vacuum to give the title
compound.
Example 457B
N-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1-
H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-e-
n-1-yl]methyl}piperazin-1-yl)benzamide
This example was prepared by substituting EXAMPLE 457A for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.24 (d, 1H), 8.83 (t, 1H), 8.56 (s, 1H), 8.38 (dd, 1H),
8.03 (d, 1H), 7.51 (d, 1H), 7.43 (d, 2H), 7.24 (m, 2H), 7.09 (d,
1H), 7.07 (d, 2H), 6.91 (dd, 1H), 6.72 (m, 2H), 3.89 (m, 1H),
3.80-3.70 (m, 1H), 3.60-3.40 (m, 4H), 3.06 (m, 1H), 3.03 (m, 4H),
2.77 (s, 2H), 2.70 (m, 1H), 2.26 (m, 2H), 2.18-2.13 (m, 5H), 2.09
(s, 3H), 1.97 (s, 2H), 1.38 (t, 2H), 0.94 (s, 6H).
Example 458
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2-y-
l]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide
Example 458A
4-((4-(methylsulfonyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamid-
e
This example was prepared by substituting methanesulfonyl chloride
for acetic anhydride in EXAMPLE 457A.
Example 458B
2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2-y-
l]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide
This example was prepared by substituting EXAMPLE 458A for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.23 (d, 1H), 8.85 (t, 1H), 8.57 (s, 1H), 8.37 (dd, 1H),
8.01 (d, 1H), 7.52 (d, 1H), 7.43 (d, 2H), 7.24 (m, 2H), 7.15 (d,
1H), 7.07 (d, 2H), 6.97 (d, 1H), 6.72 (m, 2H), 4.00-3.90 (m, 3H),
3.68-3.59 (m, 3H), 3.58-3.48 (m, 1H), 3.06-3.02 (m, 7H), 2.98-2.89
(m, 2H), 2.77 (s, 2H), 2.25 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H),
1.38 (t, 2H), 0.94 (s, 6H).
Example 459
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[6-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}me-
thoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)ben-
zamide
Example 459A
tert-butyl
4-fluoro-4-((5-sulfamoyl-3-(trifluoromethyl)pyridin-2-yloxy)met-
hyl)piperidine-1-carboxylate
This example was prepared by substituting EXAMPLE 410E for EXAMPLE
329A and EXAMPLE 419A for (tetrahydro-2H-pyran-4-yl)methanol in
EXAMPLE 329B.
Example 459B
6-((4-fluoropiperidin-4-yl)methoxy)-5-(trifluoromethyl)pyridine-3-sulfonam-
ide
This example was prepared by substituting EXAMPLE 459A for EXAMPLE
422A in EXAMPLE 422B.
Example 459C
6-((1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl)methoxy)-5-(trifluo-
romethyl)pyridine-3-sulfonamide
This example was prepared by substituting EXAMPLE 459B for EXAMPLE
422B in EXAMPLE 434A.
Example 459D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[6-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}me-
thoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)ben-
zamide
This example was prepared by substituting EXAMPLE 400E for EXAMPLE
26C and EXAMPLE 459C for EXAMPLE 1F in EXAMPLE 177. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 12.94 (d, 1H), 8.40
(d, 1H), 8.11 (d, 1H), 7.68 (m, 2H), 7.35 (d, 2H), 7.06 (d, 2H),
6.99 (d, 2H), 6.71 (dd, 1H), 6.39 (d, 1H), 6.06 (t, 1H), 4.67 (d,
2H), 4.55 (d, 2H), 4.47 (d, 2H), 3.07 (m, 5H), 2.74 (m, 6H), 2.19
(m, 6H), 1.90 (m, 6H), 1.40 (t, 2H), 0.93 (s, 6H).
Example 460
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-phenoxybenzamide
The title compound was prepared as described in EXAMPLE 177 by
replacing EXAMPLE 26C with EXAMPLE 18G. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 12.87 (s, 1H), 11.60 (s, 1H),
8.58 (s, 1H), 8.47 (d, 1H), 8.11 (s, 1H), 7.81-7.91 (m, 1H), 7.76
(dd, 1H), 7.59-7.66 (m, 1H), 7.48 (d, 1H), 7.34 (d, 2H) 7.00-7.11
(m, 5H), 6.73 (dd, 1H) 6.67 (dd, 1H), 6.08 (d, 1H), 3.85 (dd, 2H),
3.20-3.30 (m, 4H), 3.04 (s, 4H), 2.77 (s, 2H), 2.17 (d, 6H), 1.96
(s, 2H), 1.81-1.92 (m, 1H), 1.55-1.66 (m, 2H), 1.39 (t, 2H),
1.17-1.32 (m, 2H), 0.93 (s, 6H).
Example 461
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-chloro-6-(2-tetrahydrofuran-2-ylethoxy)pyridin-3-yl]sulfonyl}--
2-(1H-indazol-4-yloxy)benzamide
Example 461A
5-chloro-6-(2-(tetrahydrofuran-2-yl)ethoxy)pyridine-3-sulfonamide
This example was prepared by substituting EXAMPLE 387A for EXAMPLE
329A and 2-(tetrahydrofuran-2-yl)ethanol for
(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 329B.
Example 461B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-chloro-6-(2-tetrahydrofuran-2-ylethoxy)pyridin-3-yl]sulfonyl}--
2-(1H-indazol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 461A for EXAMPLE
1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177C. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 13.08 (s, 1H), 8.27
(d, J=2.17 Hz, 1H), 7.83 (d, J=1.83 Hz, 1H), 7.80 (s, 1H), 7.58 (d,
J=8.85 Hz, 1H), 7.36 (d, J=8.54 Hz, 2H), 7.03-7.10 (m, 4H), 6.79
(dd, J=9, 2.29 Hz, 1H), 6.54 (d, J=1.53 Hz, 1H), 6.13 (d, J=7.02
Hz, 1H), 4.41-4.47 (m, 2H), 3.91-3.94 (m, 1H), 3.71-3.80 (m, 1H),
3.56-3.63 (m, 2H), 3.25 (br s, 2H), 2.33 (br s, 2H), 2.16-2.18 (m,
2H), 1.92-2.01 (m, 5H), 1.80-1.86 (m, 2H), 1.47-1.53 (m, 1H), 1.42
(t, J=6.26 Hz, 2H), 0.94 (s, 6H).
Example 462
Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcy-
clohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyanocyclohexyl)methyl]-
amino}-3-nitrophenyl)sulfonyl]benzamide
Example 462A
2-(trans-4-(aminomethyl)cyclohexyl)acetonitrile
To a solution of tert-butyl
(trans-4-(cyanomethyl)cyclohexyl)methylcarbamate (500 mg) in
dichloromethane (5 mL) was slowly added trifluoroacetic acid (3 mL)
at 0.degree. C. The mixture was warmed to room temperature, stirred
for 1 hour. The title compound was obtained by concentration.
Example 462B
4-((trans-4-cyanocyclohexyl)methylamino)-3-nitrobenzenesulfonamide
This example was prepared by substituting EXAMPLE 462A for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.
Example 462C
Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcy-
clohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyanocyclohexyl)methyl]-
amino}-3-nitrophenyl)sulfonyl]benzamide
This example was prepared by substituting EXAMPLE 462B for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.29 (d, 1H), 8.67 (t, 1H), 8.59 (s, 1H), 8.41 (dd, 1H),
7.98 (d, 1H), 7.53 (d, 1H), 7.43 (d, 2H), 7.25 (m, 1H), 7.19 (m,
1H), 7.07 (d, 2H), 6.91 (d, 1H), 6.73-6.68 (m, 2H), 5.24 (m, 2H),
3.13 (t, 2H), 3.03 (m, 4H), 2.76 (s, 2H), 2.43 (m, 1H), 2.25 (m,
2H), 2.13 (m, 4H), 1.99-1.94 (m, 4H), 1.77 (m, H), 1.59 (m, 1H),
1.46 (m, 2H), 1.38 (t, 2H), 0.99-0.90 (m, 8H).
Example 463
2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4,4-difluorocyclohexyl)methox-
y]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1--
en-1-yl]methyl}piperazin-1-yl)benzamide
Example 463A
(4,4-difluorocyclohexyl)methanol
To a slurry of lithium aluminum hydride (0.24 g) in diethyl ether
(15 mL) was added dropwise ethyl 4,4-difluorocyclohexanecarboxylate
(1.0 g) in diethyl ether (2 mL). The reaction heated at reflux
under nitrogen for 4 hours. The reaction was cooled to 0.degree.
C., followed by the careful addition of water (0.24 mL), 4N aqueous
NaOH (0.24 mL), and water (0.72 mL). The reaction was diluted with
diethyl ether (40 mL) and stirred with sodium sulfate for 30
minutes. The mixture was filtered though diatomaceous earth and the
filtrate was concentrated to provide the title compound.
Example 463B
5-chloro-6-((4,4-difluorocyclohexyl)methoxy)pyridine-3-sulfonamide
This example was prepared by substituting EXAMPLE 463A for
(tetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 387A for EXAMPLE
329A in EXAMPLE 329B.
Example 463C
2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4,4-difluorocyclohexyl)methox-
y]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1--
en-1-yl]methyl}piperazin-1-yl)benzamide
This example was prepared by substituting EXAMPLE 463B for EXAMPLE
428D in EXAMPLE 428E. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 9.15 (d, 1H), 8.69 (m, 1H), 8.59 (s, 1H), 7.99 (d, 1H),
7.53 (d, 1H), 7.44 (d, 2H), 7.24 (m, 1H), 7.16 (m, 1H), 7.07 (d,
2H), 6.70 (m, 2H), 5.45 (m, 2H), 4.22 (d, 2H), 3.04 (m, 4H), 2.77
(s, 2H), 2.26 (m, 2H), 2.16-2.08 (m, 6H), 1.97 (s, 2H), 1.86-1.68
(m, 5H), 1.47-1.36 (m, 4H), 0.94 (m, 6H).
Example 464
N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-
-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indazol-4-yloxy)benzamide
Example 464A
3-chloro-4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide
This example was prepared by substituting
3,4-dichlorobenzenesulfonamide for EXAMPLE 329A and EXAMPLE 306C
for (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 329B.
Example 464B
N-(3-chloro-4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)phenylsulfonyl)-4-
-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl-
)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 435D for EXAMPLE
1E and EXAMPLE 464A for EXAMPLE 1F in EXAMPLE 1G.
Example 464C
N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-
-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(1H-indazol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 464B for EXAMPLE
435E in EXAMPLE 435F. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 13.15 (s, 1H), 11.74-11.31 (m,
1H), 7.85 (s, 1H), 7.67 (d, 1H), 7.62-7.49 (m, 2H), 7.35 (d, 2H),
7.22-7.09 (m, 3H), 7.05 (d, 2H), 6.80 (d, 1H), 6.53 (s, 1H), 6.23
(d, 1H), 4.26 (d, 2H), 3.79 (d, 2H), 3.62 (dd, 2H), 3.17 (s, 4H),
2.77 (d, 2H), 2.22 (d, 6H), 1.88 (dd, 6H), 1.40 (t, 2H), 0.94 (s,
6H).
Example 465
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sul-
fonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]me-
thyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide
Example 465A
methyl
2-(1H-indazol-4-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-d-
ihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate
This example was prepared by substituting EXAMPLE 400C for
tert-butyl piperazine-1-carboxylate and EXAMPLE 145E for EXAMPLE
27C in EXAMPLE 1A.
Example 465B
methyl
4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)me-
thyl)piperazin-1-yl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4--
yloxy)benzoate
This example was prepared by substituting EXAMPLE 465A for EXAMPLE
400D in EXAMPLE 435C.
Example 465C
4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)pi-
perazin-1-yl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yloxy)b-
enzoic acid
This example was prepared by substituting EXAMPLE 465B for EXAMPLE
175D in EXAMPLE 175E.
Example 465D
N-(5-chloro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-ylsulfo-
nyl)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)meth-
yl)piperazin-1-yl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl-
oxy)benzamide
This example was prepared by substituting EXAMPLE 465C for EXAMPLE
27G and EXAMPLE 404A for EXAMPLE 1F in EXAMPLE 27H.
Example 465E
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sul-
fonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]me-
thyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 465D for EXAMPLE
435E in EXAMPLE 435F, except here the final compound was purified
by preparative HPLC using a C18 column, 250.times.50 mm, 10, and
eluting with a gradient of 20-100% CH.sub.3CN vs. 0.1%
trifluoroacetic acid in water, followed by column chromatography
eluting with 98/2 dichloromethane/methanol. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 13.13 (s, 1H), 8.28 (d, 1H),
7.90 (d, 1H), 7.83 (s, 1H), 7.58 (d, 1H), 7.39 (d, 2H), 7.17 (d,
2H), 7.08 (m, 2H), 6.82 (dd, 1H), 6.57 (d, 1H), 6.14 (d, 1H), 4.52
(d, 2H), 4.15 (s, 2H), 3.80 (m, 2H), 3.60 (m, 2H), 3.20 (v br m,
4H), 2.98 (v br s, 2H), 2.35 (v br m, 4H), 2.18 (s, 2H), 1.87 (m,
4H), 1.20 (s, 6H).
Example 466
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-cyano-6-(2-tetrahydro-2H-pyran-4-ylethoxy)pyridin-3-yl]sulfony-
l}-2-(1H-indazol-4-yloxy)benzamide
Example 466A
5-bromo-6-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)pyridine-3-sulfonamide
This example was prepared by substituting
2-(tetrahydro-2H-pyran-4-yl)ethanol for
(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 329B.
Example 466B
5-cyano-6-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)pyridine-3-sulfonamide
This example was prepared by substituting EXAMPLE 466A for EXAMPLE
329A in EXAMPLE 333A.
Example 466C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-cyano-6-(2-tetrahydro-2H-pyran-4-ylethoxy)pyridin-3-yl]sulfony-
l}-2-(1H-indazol-4-yloxy)benzamide
This example was prepared by substituting EXAMPLE 466B for EXAMPLE
1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177C. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 13.04 (s, 1H), 8.48
(d, 1H), 8.13 (s, 1H), 7.75 (s, 1H), 7.62 (d, 1H), 7.37 (d, 2H),
7.01-7.08 (m, 4H), 6.76 (dd, 1H), 6.51 (d, 1H), 6.08 (d, 1H), 4.47
(t, 2H), 3.81-3.85 (m, 2H), 3.71-3.80 (m, 1H), 2.18 (m, 2H), 1.99
(m, 2H), 1.62-1.72 (m, 5H), 1.42 (t, 2H), 1.23 (m, 2H), 0.94 (s,
6H).
Example 467
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-
-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide
Example 467A
4-((1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)-3-nitrobenzenes-
ulfonamide
This EXAMPLE was prepared by substituting
(1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine for
1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A.
Example 467B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-
-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide
This EXAMPLE was prepared by substituting EXAMPLE 26C for EXAMPLE
1E and EXAMPLE 467A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.47 (br s, 1H), 11.17 (s,
1H), 9.43 (br s, 1H), 8.69 (d, 1H), 8.62 (d, 1H), 7.90 (dd, 1H),
7.52 (d, 1H), 7.40 (m, 3H), 7.15 (d, 1H), 7.06 (m, 3H), 6.85 (dd,
1H), 6.68 (m, 1H), 6.39 (t, 1H), 6.19 (br s, 1H), 4.01 (m, 1H),
3.91 (m, 2H), 3.58 (m, 3H), 3.01 (m, 3H), 2.73 (m, 5H), 2.32 (m,
6H), 2.16 (m, 6H), 2.0 (m, 2H), 1.45 (m, 2H), 0.94 (s, 6H).
Example 468
N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-ph-
enoxy-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1-
]hept-3-yl]amino}piperidin-1-yl)benzamide
Example 468A
methyl
2-phenoxy-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzoate
1,4-dioxa-8-azaspiro[4.5]decane (1.18 g), methyl
4-fluoro-2-phenoxybenzoate (1.85 g), and K.sub.2CO.sub.3 (1.14 g)
was stirred at 125.degree. C. in dimethylsulfoxide (25 mL) for 24
hours. The mixture was cooled, poured into 300 mL water, extracted
three times with ether, and the ether extracts were combined,
rinsed three times with water, and brine, and concentrated. The
residue was chromatographed on silica gel using 10-30% ethyl
acetate in hexanes as eluent to give the title compound.
Example 468B
methyl 4-(4-oxopiperidin-1-yl)-2-phenoxybenzoate
EXAMPLE 468A (23.7 g) was heated to 80.degree. C. in a mixture of
acetic acid (30 mL), tetrahydrofuran (40 mL) and water (30 mL) for
24 hours. The mixture was cooled and concentrated. The crude
product was chromatographed on silica gel using 25% ethyl acetate
in hexanes as the eluent to give the title compound.
Example 468C
methyl
2-phenoxy-4-(4-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-
-ylamino)piperidin-1-yl)benzoate
EXAMPLE 468B (0.99 g) and
(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine (0.51 mL)
were refluxed in 200 mL methanol under a Dean-Stark trap for 24
hours. The solvent was boiled off to a volume of 75 mL, and the
mixture was cooled to room temperature. NaBH.sub.4 (0.115 g) was
added and the mixture was stirred for 30 minutes. The reaction was
quenched with 10 mL water, partially concentrated, and
chromatographed on silica gel using 1% triethylamine in ethyl
acetate as eluent to give the title compound.
Example 468D
methyl
2-phenoxy-4-(4-(3-phenyl-N-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.-
1.1]heptan-3-yl)propanamido)piperidin-1-yl)benzoate
EXAMPLE 468C (320 mg), 3-phenylpropanoyl chloride (0.113 mL), and
triethylamine (0.116 mL) were stirred in dichloromethane (15 mL)
for 24 hours. The reaction mixture was partially concentrated and
the residue was chromatographed on silica gel using 20% ethyl
acetate in hexanes as eluent to give the title compound.
Example 468E
2-phenoxy-4-(4-(3-phenyl-N-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hep-
tan-3-yl)propanamido)piperidin-1-yl)benzoic acid
This EXAMPLE was prepared by substituting EXAMPLE 468D for EXAMPLE
1D in EXAMPLE 1E.
Example 468F
N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-ph-
enoxy-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1-
]hept-3-yl]amino}piperidin-1-yl)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 468E for EXAMPLE
1E in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.32 (m, 2H), 7.64 (m, 2H), 7.11-7.29 (m, 6H), 6.95 (dd,
1H), 6.89 (dd, 1H), 6.70 (m, 3H), 6.32 (m, 1H), 3.85 (m, 3H), 3.70
(m, 3H), 2.91 (m, 6H), 2.65-2.80 (m, 6H), 1.91 (s, 6H), 1.61 (m,
4H), 1.16-1.36 (m, 4H), 1.11 (m, 6H), 0.95 (m, 4H), 0.87 (d,
2H).
Example 469
N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxy-4--
(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3--
yl]amino}piperidin-1-yl)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 468E for EXAMPLE
1E and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 8.72 (m, 1H), 8.44 (d, 1H),
7.73 (dd, 1H), 7.54 (m, 1H), 7.12-7.28 (m, 6H), 7.05 (dd, 1H), 6.95
(dd, 1H), 6.82 (d, 1H), 6.74 (m, 2H), 6.34 (m, 1H), 3.77 (m, 2H),
3.63 (m, 4H), 3.10 (m, 4H), 3.05 (m, 4H), 2.78 (m, 6H), 1.75-2.10
(m, 8H), 1.55 (m, 2H), 1.40 (m, 2H), 1.19 (m, 6H), 1.01 (m, 2H),
0.95 (m, 2H), 0.88 (d, 2H).
Example 470
N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-ph-
enoxy-4-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]he-
pt-3-yl]amino}piperidin-1-yl)benzamide
Example 470A
methyl
2-phenoxy-4-(4-((3-phenylpropyl)((1S,2S,3S,5R)-2,6,6-trimethylbicyc-
lo[3.1.1]heptan-3-yl)amino)piperidin-1-yl)benzoate
EXAMPLE 468C 320 mg), 3-phenylpropanal (111 mg), and
NaBH(OAc).sub.3 (205 mg) were stirred in dichloromethane (15 mL)
for 24 hours. The reaction mixture was chromatographed on silica
gel using 20% ethyl acetate in hexanes as eluent to give the title
compound.
Example 470B
2-phenoxy-4-(4-((3-phenylpropyl)((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.-
1]heptan-3-yl)amino)piperidin-1-yl)benzoic acid
This EXAMPLE was prepared by substituting EXAMPLE 470A for EXAMPLE
1D in EXAMPLE 1E.
Example 470C
N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-ph-
enoxy-4-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]he-
pt-3-yl]amino}piperidin-1-yl)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 470B for EXAMPLE
1E in EXAMPLE 1G. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.57 (m, 1H), 8.47 (d, 1H), 7.50 (m, 1H), 7.32 (m, 1H),
7.12-7.31 (m, 7H), 6.99 (dd, 1H), 6.81 (m, 3H), 6.37 (d, 1H), 4.44
(t, 1H), 3.84 (m, 4H), 3.37 (m, 2H), 3.25 (m, 2H), 3.06 (m, 2H),
2.70 (m, 4H), 2.57 (m, 4H), 1.82 (m, 2H), 1.77 (m, 4H), 1.52-1.71
(m, 8H), 1.25 (m, 3H), 1.15 (s, 3H), 0.95 (d, 2H), 0.93 (s, 3H),
0.74 (d, 2H).
Example 471
N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxy-4--
(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-
amino}piperidin-1-yl)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 470B for EXAMPLE
1E and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 8.68 (m, 1H), 8.40 (d, 1H),
7.70 (dd, 1H), 7.55 (d, 1H), 7.11-7.29 (m, 7H), 7.01 (dd, 1H), 6.95
(dd, 1H), 6.76 (d, 2H), 6.34 (m, 1H), 3.75 (m, 2H), 3.61 (m, 4H),
3.43 (m, 4H), 3.05 (m, 6H), 2.75 (m, 2H), 2.60 (m, 2H), 2.41 (m,
4H), 2.15 (m, 1H), 1.82 (m, 4H), 1.69 (m, 2H), 1.51 (m, 1H), 1.18
(m, 8H), 0.96 (m, 1H), 0.94 (s, 3H).
Example 472
4-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)pipera-
zin-1-yl]-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2--
phenoxybenzamide
Example 472A
Ethyl 4-fluoro-2-phenoxybenzoate (600 mg) and piperazine (596 mg)
were dissolved in anhydrous dimethyl sulfoxide and heated at
130.degree. C. overnight. The reaction mixture was cooled to room
temperature and diluted with ethyl acetate. The organic phase was
washed with water and brine, dried over anhydrous sodium sulfate,
filtered, and concentrated to afford the title compound.
Example 472B
EXAMPLE 472A (400 mg), 1-(bromomethyl)-2-nitrobenzene (277 mg) and
sodium carbonate (408 mg) were suspended in anhydrous
N,N-dimethylformamide (20 mL). The reaction mixture was stirred at
room temperature for 4 hours. The reaction mixture was diluted with
ethyl acetate. The organic phase was washed with water and brine,
dried over anhydrous sodium sulfate, filtered, and concentrated.
Flash column purification with 10-40% ethyl acetate/hexane to
afford the title compound.
Example 472C
A solution of EXAMPLE 472B (0.6 g) in methanol (20 ml) was added to
Ra--Ni, solvent washed (0.480 g) in a 250 mL pressure bottle and
stirred for 3 hours at 30 psi at room temperature. The mixture was
filtered through a nylon membrane and concentrated to afford the
product.
Example 472D
This EXAMPLE was prepared by substituting
(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-one for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 472C for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 472E
This EXAMPLE was prepared by substituting EXAMPLE 472D for EXAMPLE
175D in EXAMPLE 175E.
Example 472F
4-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)pipera-
zin-1-yl]-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2--
phenoxybenzamide
This EXAMPLE was prepared by substituting EXAMPLE 472E for EXAMPLE
27G and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.66 (bs, 1H), 9.90 (bs,
1H), 9.56 (s, 1H), 8.69 (t, 1H), 8.50 (d, 1H), 7.81 (dd, 1H), 7.54
(d, 1H), 7.22 (m, 5H), 7.01 (m, 1H), 6.83 (m, 3H), 6.47 (s, 1H),
3.84 (m, 4H), 3.65 (d, 6H), 3.54 (m, 4H), 3.43 (m, 2H), 3.19 (m,
8H), 2.68 (d, 3H), 2.34 (m, 2H), 2.25 (m, 4H), 1.99 (m, 4H).
Example 473
4-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)pipera-
zin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulf-
onyl)-2-phenoxybenzamide
This EXAMPLE was prepared by substituting EXAMPLE 472E for EXAMPLE
27G in EXAMPLE 27H. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.61 (bs, 1H), 9.38 (bs, 1H),
8.64 (s, 1H), 8.47 (d, 1H), 7.75 (dd, 1H), 7.55 (d, 1H), 7.23 (t,
3H), 7.15 (d, 2H), 6.98 (t, 1H), 6.82 (d, 3H), 6.47 (s, 2H), 3.85
(m, 6H), 3.31 (m, 12H), 2.68 (d, 3H), 2.06 (m, 9H), 1.62 (m, 2H),
1.29 (m, 2H).
Example 474
4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-N-({3-nitro-4--
[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide
Example 474A
2-Fluorobenzaldehyde (264 mg), (1S,5S)-3-azabicyclo[3.2.2]nonane
(500 mg) and sodium carbonate (846 mg) were suspended in anhydrous
dimethylsulfoxide (3 mL). The reaction mixture was heated at
135.degree. C. overnight. The reaction mixture was cooled to room
temperature and diluted with ethyl acetate. The organic phase was
washed with water and brine, dried over anhydrous sodium sulfate,
filtered, and concentrated. Flash column purification with 0-10%
ethyl acetate/hexane provided the title compound.
Example 474B
This EXAMPLE was prepared by substituting EXAMPLE 474A for
4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 113A for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
Example 474C
This EXAMPLE was prepared by substituting EXAMPLE 474B for EXAMPLE
175D in EXAMPLE 175E.
Example 474D
4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-N-({3-nitro-4--
[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide
This EXAMPLE was prepared by substituting EXAMPLE 474C for EXAMPLE
27G in EXAMPLE 27H. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.74 (bs, 1H), 8.64 (t, 1H),
8.47 (d, 1H), 7.76 (dd, 1H), 7.54 (m, 2H), 7.43 (d, 2H), 7.23 (m,
3H), 7.15 (d, 1H), 6.98 (t, 1H), 6.83 (m, 3H), 6.53 (d, 1H), 4.45
(bs, 2H), 3.87 (m, 4H), 3.30 (m, 6H), 3.06 (m, 8H), 1.89 (m, 7H),
1.64 (m, 6H), 1.29 (m, 2H).
Example 475
4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-2-phenoxy-N-({-
4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phe-
nyl}sulfonyl)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 474C for EXAMPLE
27G and EXAMPLE 163A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.78 (bs, 1H), 8.11
(d, 1H), 7.86 (dd, 1H), 7.54 (d, 2H), 7.44 (d, 2H), 7.28 (m, 4H),
7.11 (d, 1H), 7.04 (m, 1H), 6.85 (m, 3H), 6.53 (d, 1H), 4.46 (m,
2H), 3.86 (m, 4H), 3.28 (m, 6H), 3.10 (m, 4H), 2.98 (d, 4H), 1.97
(s, 2H), 1.84 (m, 5H), 1.64 (m, 6H), 1.26 (m, 2H).
Example 476
4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-2-phenoxy-N-({-
4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 474C for EXAMPLE
27G and EXAMPLE 2A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.19 (bs, 1H), 9.83 (bs,
1H), 7.52 (m, 6H), 7.33 (m, 3H), 7.12 (t, 1H), 6.93 (d, 2H), 6.83
(m, 1H), 6.56 (d, 2H), 6.47 (d, 1H), 4.47 (s, 2H), 3.85 (m, 4H),
3.26 (m, 2H), 3.11 (m, 4H), 2.96 (m, 6H), 1.97 (s, 2H), 1.81 (m,
6H), 1.64 (m, 7H), 1.22 (m, 2H).
Example 477
4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-N-({4-[(3-morp-
holin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide
This EXAMPLE was prepared by substituting EXAMPLE 474C for EXAMPLE
27G and EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 11.77 (bs, 1H), 10.04 (bs,
1H), 8.69 (t, 1H), 8.50 (d, 1H), 7.81 (dd, 1H), 7.55 (d, 2H), 7.43
(d, 2H), 7.24 (m, 3H), 7.15 (d, 1H), 7.01 (t, 1H), 6.84 (m, 3H),
6.52 (d, 1H), 4.44 (s, 2H), 3.97 (s, 2H), 3.54 (m, 6H), 3.39 (m,
4H), 3.19 (m, 8H), 2.97 (d, 4H), 1.99 (m, 4H), 1.83 (m, 4H), 1.64
(m, 4H).
Example 478
4-(4-{2-[(4R,7S)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoinden-5-yl]benzyl}p-
iperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl-
}sulfonyl)-2-phenoxybenzamide
Example 478A
4-(4-Methoxycarbonyl-3-phenoxy-phenyl)-piperazine-1-carboxylic acid
tert-butyl ester
This EXAMPLE was prepared by substituting piperazine-1-carboxylic
acid tert-butyl ester for EXAMPLE 1B in EXAMPLE 1D.
Example 478B
4-(4-Carboxy-3-phenoxy-phenyl)-piperazine-1-carboxylic acid
tert-butyl ester
This EXAMPLE was prepared by substituting EXAMPLE 478A for EXAMPLE
1D in EXAMPLE 1E.
Example 478C
4-(4-{3-Nitro-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-benzenesulfonylamino-
carbonyl}-3-phenoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl
ester
This EXAMPLE was prepared by substituting EXAMPLE 478B for EXAMPLE
1E in EXAMPLE 1G.
Example 478D
3-Nitro-N-(2-phenoxy-4-piperazin-1-yl-benzoyl)-4-[(tetrahydro-pyran-4-ylme-
thyl)-amino]-benzenesulfonamide
This EXAMPLE was prepared by substituting EXAMPLE 478C for EXAMPLE
1A in EXAMPLE LB to isolate the title compound as the mono
trifluoroacetic acid salt.
Example 478E
Trifluoromethanesulfonic acid
(4R,7S)-(2,3,3a,4,7,7a-hexahydro-1H-4,7-methano-inden-5-yl)
ester
(4R,7R)-octahydro-4,7-methano-inden-5-one (2.00 g) was dissolved in
tetrahydrofuran (25 mL) and cooled to -78.degree. C. using an
isopropyl alcohol/dry ice bath. Sodium bis(trimethylsilyl)-amide
(1M in tetrahydrofuran, 14.65 mL) was added slowly. The solution
was allowed to warm to room temperature, stirred for one hour,
cooled to -78.degree. C. using an isopropyl alcohol/dry ice bath,
and N-phenyltrifluoromethanesulfonimide (5.23 g) was added. The
solution was allowed to warm to room temperature and stir for 16
hours. Hexane was added and the solution was stirred at room
temperature for one hour, filtered, and the solvent removed under
vacuum.
Example 478F
(4R,7S)-2-(2,3,3a,4,7,7a-Hexahydro-1H-4,7-methano-inden-5-yl)-benzaldehyde
EXAMPLE 478E (941 mg), 2-formylphenylboronic acid (600 mg), and
potassium phosphate tribasic (1416 mg) were added to
tetrahydrofuran (20 mL). The solution was degasses and flushed with
nitrogen three times. Tetrakis(triphenylphosphine)palladium(O) (244
mg) was added and the solution was heated at 60.degree. C. for 16
hours. The solution was cooled, added to water, and extracted with
50% ethyl acetate (hexanes). The extract was washed with brine,
dried on anhydrous sodium sulfate, concentrated and purified by
flash column chromatography on silica gel using 10% ethyl acetate
(hexanes).
Example 478G
4-(4-{2-[(4R,7S)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoinden-5-yl]benzyl}p-
iperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl-
}sulfonyl)-2-phenoxybenzamide
EXAMPLE 478D (200 mg), EXAMPLE 478F (74 mg), and sodium
cyanoborohydride resin (2.15 mmol/g, 144 mg) were added to
tetrahydrofuran (3 mL) and acetic acid (0.7 mL) and stirred at room
temperature for 16 hours. The solution was concentrated on vacuum
and purified by flash column chromatography on silica gel using 5%
methanol (dichloromethane) to provide the title compound as the
mono acetic acid salt. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.94 (bs, 1H), 8.64 (t, 1H),
8.48 (d, 1H), 7.76 (dd, 1H), 7.51 (d, 1H), 7.40 (m, 1H), 7.27-7.18
(m, 5H), 7.16 (d, 1H), 6.99 (tt, 1H), 6.83 (dt, 2H), 6.78 (dd, 1H),
6.41 (d, 1H), 6.23 (d, 1H), 3.87 (dd, 2H), 3.50 (m, 2H), 3.34 (t,
2H), 3.21 (bs, 4H), 2.73 (bs, 1H), 2.63 (bs, 1H), 2.46 (m, 4H),
2.11 (m, 2H), 1.95-1.75 (m, 4H), 1.91 (s, 3H), 1.66-1.52 (m, 6H),
1.28 (m, 2H), 1.02 (m, 2H), 0.85 (m, 1H).
Example 479
4-[4-(2-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzyl)pi-
perazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-
sulfonyl)-2-phenoxybenzamide
Example 479A
tert-butyl
4-(4-(methoxycarbonyl)-3-phenoxyphenyl)piperazine-1-carboxylate
This EXAMPLE was prepared by substituting tert-butyl
piperazine-1-carboxylate for EXAMPLE 1B in EXAMPLE 1D.
Example 479B
4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-phenoxybenzoic acid
This EXAMPLE was prepared by substituting EXAMPLE 479A for EXAMPLE
1D in EXAMPLE 1E.
Example 479C
tert-butyl
4-(4-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsu-
lfonylcarbamoyl)-3-phenoxyphenyl)piperazine-1-carboxylate
This EXAMPLE was prepared by substituting EXAMPLE 479B for EXAMPLE
1E in EXAMPLE 1G.
Example 479D
N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)-2-phen-
oxy-4-(piperazin-1-yl)benzamide
This EXAMPLE was prepared by substituting EXAMPLE 479C for EXAMPLE
1A in EXAMPLE 1B.
Example 479E
2-((4-(4-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylc-
arbamoyl)-3-phenoxyphenyl)piperazin-1-yl)methyl)phenylboronic
acid
EXAMPLE 479D (213 mg), 2-formylphenylboronic acid (54 mg), and
sodium cyanoborohydride resin (2.38 mmol/g, 252 mg) were added to
tetrahydrofuran (3.5 mL) and acetic acid (1.1 mL), and the solution
was stirred at room temperature for 16 hours. The solution was
purified by flash column chromatography on silica gel with 1%
acetic acid and 10% methanol in dichloromethane.
Example 479F
8-((5-bromothiophen-2-yl)methyl)-8-azabicyclo[3.2.1]octane
hydrochloride
This EXAMPLE was prepared by substituting
5-bromothiophene-2-carbaldehyde for
4'-chlorobiphenyl-2-carboxaldehyde and 8-azabicyclo[3.2.1]octane
hydrochloride for tert-butyl piperazine-1-carboxylate in EXAMPLE
1A.
Example 479G
4-(4-(2-(5-(8-azabicyclo[3.2.1]octan-8-ylmethyl)thiophen-2-yl)benzyl)piper-
azin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfo-
nyl)-2-phenoxybenzamide
EXAMPLE 479E (80 mg), EXAMPLE 479F (42.5 mg),
bis(triphenylphosphine)palladium(II) dichloride (7.7 mg), and
lithium hydroxide (10.5 mg) were combined in a mixture of
dimethoxyethane (1.6 mL), methanol (0.5 mL) and water (0.7 mL) in a
microwave vial. The reaction mixture was heated in a CEM Discover
microwave reactor at 150.degree. C. for 15 minutes. The crude
material was purified by flash chromatography eluting with a
gradient of 1% methanol/dichloromethane to 5%
methanol/dichloromethane. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.33 (m, 2H), 7.64 (m, 2H), 7.44
(m, 1H), 7.39 (m, 1H), 7.32 (m, 2H), 7.12 (m, 3H), 6.90 (m, 2H),
6.85 (t, 1H), 6.68 (m, 3H), 6.30 (d, 1H), 3.83 (dd, 2H), 3.65 (s,
2H), 3.51 (s, 2H), 3.17 (m, 4H), 3.08 (m, 4H), 2.45 (m, 6H), 1.92
(m, 2H), 1.62 (m, 4H), 1.54 (m, 3H), 1.28 (m, 6H).
Example 480
4-[4-(2-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzylide-
ne)piperidin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]ph-
enyl}sulfonyl)-2-phenoxybenzamide
Example 480A
methyl
2-phenoxy-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzoate
Methyl 4-fluoro-2-phenoxybenzoate (2 g) and
1,4-dioxa-8-azaspiro[4.5]decane (1.279 g) were combined in
dimethylsulfoxideO (12 mL) in a 250 mL round-bottom flask. Sodium
carbonate (1.291 g) was added. The reaction flask was sealed and
heated to 130.degree. C. overnight. The reaction mixture was
diluted with ethyl acetate, washed thoroughly with water and with
brine, and dried over MgSO.sub.4, filtered and concentrated to
obtain the desired product.
Example 480B
methyl 4-(4-oxopiperidin-1-yl)-2-phenoxybenzoate
EXAMPLE 480A was taken up in acetic acid (30%, 20 mL) and
tetrahydrofuran (10 mL). The reaction mixture was heated to
75.degree. C. overnight. The volume was reduced under vacuum and
the residue was neutralized with sodium hydroxide solution, and
extracted with ethyl acetate. The extracts were washed with water
and with brine, dried over MgSO.sub.4, filtered and concentrated
under vacuum to obtain the desired product.
Example 480C
methyl
4-(4-(2-bromobenzylidene)piperidin-1-yl)-2-phenoxybenzoate
Dimethylsulfoxide (22.88 mL) with sodium hydride (0.332 g) was
heated to 70 OC for 1 hour, then cooled to room temperature and
(2-bromobenzyl)triphenylphosphonium bromide (3.40 g) was added in
several portions, and then stirred at room temperature for 1 hour.
A solution of methyl 4-(4-oxopiperidin-1-yl)-2-phenoxybenzoate (1.8
g) in dimethylsulfoxide (5.20 mL) was then added and the reaction
was heated to 70.degree. C. over the weekend. The reaction was
acidified with 1M aqueous HCl solution and extracted with ether.
The combined extracts were washed thoroughly with water and brine,
dried over MgSO.sub.4, filtered and concentrated under vacuum. The
residue was purified by flash chromatography eluting with 0-20%
ethyl acetate in hexanes.
Example 480D
methyl
2-phenoxy-4-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benz-
ylidene)piperidin-1-yl)benzoate
EXAMPLE 480C (259 mg), bis(pinacolato)diboron (206 mg),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
dichloromethane (22 mg), and potassium acetate (159 mg) were
combined in dimethyl sulfoxide (2.7 mL). The reaction was heated to
90.degree. C. for 36 hours. The reaction mixture was diluted with
ethyl acetate, washed thoroughly with water and with brine, and
dried over MgSO.sub.4, filtered and concentrated under vacuum. The
crude solid was washed with hexanes and with hexanes/ether (2:1) to
obtain the desired product.
Example 480E
4-(4-(2-(5-(8-azabicyclo[3.2.1]octan-8-ylmethyl)thiophen-2-yl)benzylidene)-
piperidin-1-yl)-2-phenoxybenzoic acid
This EXAMPLE was prepared by substituting EXAMPLE 480D for EXAMPLE
479E in EXAMPLE 479G.
Example 480F
4-(4-(2-(5-(8-azabicyclo[3.2.1]octan-8-ylmethyl)thiophen-2-yl)benzylidene)-
piperidin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenyl-
sulfonyl)-2-phenoxybenzamide
This EXAMPLE was prepared by substituting EXAMPLE 480E for EXAMPLE
1E in EXAMPLE 1G. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.54 (s, 1H), 9.36 (br s, 1H), 8.48 (d, 1H), 7.76 (dd,
1H), 7.53 (m, 2H), 7.34 (m, 3H), 7.25 (m, 4H), 7.16 (d, 1H), 7.00
(t, 1H), 6.84 (d, 2H), 6.81 (dd, 1H), 6.44 (d, 1H), 6.37 (br s,
1H), 4.36 (d, 2H), 3.85 (m, 3H), 3.44 (m, 2H), 3.28 (m, 6H), 2.36
(m, 3H), 2.23 (m, 4H), 1.90 (m, 3H), 1.81 (m, 2H), 1.62 (m, 5H),
1.47 (m, 1H), 1.29 (m, 2H).
Example 481
4-[4-(3-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzyl)pi-
perazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-
sulfonyl)-2-phenoxybenzamide
Example 481A
3-((4-(4-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylc-
arbamoyl)-3-phenoxyphenyl)piperazin-1-yl)methyl)phenylboronic
acid
This EXAMPLE was prepared by substituting 3-formylphenylboronic
acid for 2-formylphenylboronic acid in EXAMPLE 479E.
Example 481B
4-(4-(3-(5-(8-azabicyclo[3.2.1]octan-8-ylmethyl)thiophen-2-yl)benzyl)piper-
azin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfo-
nyl)-2-phenoxybenzamide
This EXAMPLE was prepared by substituting EXAMPLE 481A for EXAMPLE
479E in EXAMPLE 479G. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.76 (br s, 1H), 9.55 (br s,
1H), 8.55 (t, 1H), 8.46 (d, 1H), 7.75 (m, 2H), 7.54 (m, 2H), 7.40
(m, 1H), 7.20 (m, 4H), 6.97 (m, 1H), 6.86 (m, 1H), 6.82 (m, 3H),
6.55 (m, 1H), 4.41 (d, 2H), 3.88 (m, 6H), 3.43 (m, 3H), 3.30 (m,
6H), 3.06 (m, 6H), 1.90 (m, 4H), 1.65 (m, 5H), 1.30 (m, 3H).
SEQUENCE LISTINGS
1
1116PRTArtificial SequenceProbe Peptide 1Gly Gln Val Gly Arg Gln
Leu Ala Ile Ile Gly Asp Lys Ile Asn Arg 1 5 10 15
* * * * *
References